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Depression of serum melatonin in patients with primary breast cancer is not due to an increased peripheral metabolism
Abstract
Serum melatonin and its main metabolic product 6-sulfatoxymelatonin were determined in 17 patients with breast cancer (BC) with either a fresh primary tumor (nine) or a secondary tumor (eight) as well as in four patients with untreated benign breast disease (controls). Circadian rhythms were detected in all groups with acrophases around 2 AM for melatonin and around 3 AM for 6-sulfatoxymelatonin. The nocturnal melatonin and 6-sulfatoxymelatonin concentrations were significantly depressed in the group of patients with primary breast cancer compared with controls (P less than 0.01, P less than 0.025). The circadian amplitudes of melatonin and 6-sulfatoxymelatonin were also depressed by 81% (P less than 0.01) and 63% (P less than 0.01). In contrast, patients with secondary BC had nocturnal melatonin and 6-sulfatoxymelatonin concentrations and amplitudes similar to controls. These results demonstrate that the depression of circulating melatonin in patients with primary BC is not due to an enhanced degradation to 6-sulfatoxymelatonin in the liver but must be due to a reduced activity of the pineal gland.
... Among the above-mentioned retrospective case-control studies, several of them registered in the blood and/or urine of patients suffering from breast cancer a lower melatonin or melatonin metabolite concentrations compared with breast cancer-free women [34][35][36][37]. In particular, a study [36] on the correlation between main melatonin metabolite excretion and plasma melatonin suggested that the lower levels registered in breast cancer patients were due to the lower pineal gland hormone secretion, rather than to an increase in peripheral metabolism. ...
... Among the above-mentioned retrospective case-control studies, several of them registered in the blood and/or urine of patients suffering from breast cancer a lower melatonin or melatonin metabolite concentrations compared with breast cancer-free women [34][35][36][37]. In particular, a study [36] on the correlation between main melatonin metabolite excretion and plasma melatonin suggested that the lower levels registered in breast cancer patients were due to the lower pineal gland hormone secretion, rather than to an increase in peripheral metabolism. One of the earlier studies considered [38] also found nighttime plasma melatonin levels to be lower in estrogen receptor-positive breast cancer patients compared with estrogen receptornegative breast cancer patients as well as healthy control women. ...
... It is difficult to relate such findings to both breast cancer patients and breast cancer-free control subjects, since a series of factors-such as the disease itself, treatment, and/or behavioral changes-which might occur after the diagnosis or before surgery/treatment may actually affect melatonin blood levels. Indeed, several studies found melatonin secretion to be positively or negatively associated with the severity of the disease in terms of tumor size [37], depending on whether the cancer has metastasized [43], as well as whether the patients suffered from primary or secondary tumors or not [36]. It is to be said, however, that such studies were performed on a rather limited sample, and some of them did not even include adequate steps to exclude potential confounding effects relating to age, parity, medication use, or body mass index. ...
The aim of this article was to perform a systematic review on the role of melatonin in the prevention of cancer tumorigenesis-in vivo and in vitro-as well as in the management of cancer correlates, such as sleep-wake and mood disturbances. The International Agency for Research on Cancer recently classified "shift-work that involves circadian disruption" as "probably carcinogenic to humans" (Group 2A) based on "limited evidence in humans for the carcinogenicity of shift-work that involves night-work", and "sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)". The clinical implications and the potential uses of melatonin in terms of biologic clock influence (e.g. sleep and mood), immune function, cancer initiation and growth, as well as the correlation between melatonin levels and cancer risk, are hereinafter recorded and summarized. Additionally, this paper includes a description of the newly discovered effects that melatonin has on the management of sleep-wake and mood disturbances as well as with regard to cancer patients' life quality. In cancer patients depression and insomnia are frequent and serious comorbid conditions which definitely require a special attention. The data presented in this review encourage the performance of new clinical trials to investigate the possible use of melatonin in cancer patients suffering from sleep-wake and mood disturbances, also considering that melatonin registered a low toxicity in cancer patients.
... Seven days after DMBA treatment of Female Sprague-Dawley rats, nocturnal plasma Melatonin concentrations were depressed by 31-37 % [37]. Also, a depression of nocturnal circulating Melatonin in patients with Primary Breast Cancer has been documented [38][39]. Apparently, this decrease in Melatonin concentration is not due to an increased peripheral metabolism of Melatonin since both nocturnal Melatonin and its main metabolic product 6sulfatoxymelatonin were significantly lowered in patients with Primary Breast Cancer [39]. ...
... Also, a depression of nocturnal circulating Melatonin in patients with Primary Breast Cancer has been documented [38][39]. Apparently, this decrease in Melatonin concentration is not due to an increased peripheral metabolism of Melatonin since both nocturnal Melatonin and its main metabolic product 6sulfatoxymelatonin were significantly lowered in patients with Primary Breast Cancer [39]. Therefore, the decrease in nocturnal serum Melatonin concentration is not due to an enhanced degradation to 6-sulfatoxymelatonin in the liver but must be due to reduced activity, for an unknown reason, of the pineal gland [39].Interestingly, it has been shown that the administration of Melatonin markedly reduces the percentage of tumor-bearing animals after administration of DMBA [11]; also, the latency period was increased and the number of tumors per tumor-bearing animal was significantly reduced by a long term melatonin treatment [11]. ...
... Apparently, this decrease in Melatonin concentration is not due to an increased peripheral metabolism of Melatonin since both nocturnal Melatonin and its main metabolic product 6sulfatoxymelatonin were significantly lowered in patients with Primary Breast Cancer [39]. Therefore, the decrease in nocturnal serum Melatonin concentration is not due to an enhanced degradation to 6-sulfatoxymelatonin in the liver but must be due to reduced activity, for an unknown reason, of the pineal gland [39].Interestingly, it has been shown that the administration of Melatonin markedly reduces the percentage of tumor-bearing animals after administration of DMBA [11]; also, the latency period was increased and the number of tumors per tumor-bearing animal was significantly reduced by a long term melatonin treatment [11]. ...
A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded, during the la- tency phase, by a series of neuroendocrine disturbances, including attenuation of the preovulatory Luteinizing Hormone surge and Gonadotropin-Releasing Hormone release and amplification of the preovulatory 17� -Estradiol (E2) surge. Also, E2 treatment leads to a complete blunting of the Isoproterenol-induced stimulation of Melatonin secretion.In this study, we examined the hypothesis that Tamoxifen, an antagonist of E2, would stimulate the Isoproterenol-induced Mela- tonin (MT) secretion from the pineal gland, during the latency phase. Sprague-Dawley rats, 55-60 days of age, received, on the Estrous day of the Estrous cycle, a single dose of 15 mg DMBA delivered by intragastric intubation. In order to avoid possible interactions with endogenous steroids or mammary tumor- derived compounds, they were ovariectomized 5 days later and, one month later, sacrificed by decapitation at 10 a.m. Then, pineal glands were removed and placed in perifusion chambers containing Hanks 199 medium. The medium was satured with O2/CO2 (95 %/5 %) and its pH was 7.4. Ten independent chambers were immersed in a water bath at 37°C. Each pineal gland received medium (flow rate : 0.16 ml/min) through a system of input lines. The fractions were collected every 10 min, and immediately frozen at -20°C until Melatonin RIA. Experiments were repeated to obtain up to five ex- perimental points for each treatment. Tamoxifen (10 -9 to 10 -7 M) was applied during the entire perifusion period (7 hours). Isoproterenol (10 -6 M) was applied for 20 min after 3 hours in perifusion. Melatonin concentrations and Areas Under the Curves were compared using two-factor ANOVA as well as parametric or nonparametric two-sample methods after test- ing sample normality. In vehicle treated rats, Tamoxifen treatment, at the concentration of 10 -9 M, leads to a non significant amplification of the Isoproterenol-induced stimulation of Melatonin secretion. In DMBA-treated rats, Tamoxifen treatment leads,starting from 10 -9 M to a dose- dependent increase (up to 400% in- crease) of the Isoproterenol-induced stimulation of Melatonin . The results suggest that in addition to the well documented beneficial effects of Tamoxifen at the mammary gland level, this E2 antagonist may also have, after DMBA treatment, an additional beneficial effect at the pineal gland level through- out the stimulation of Melatonin, which exerts an inhibitory action on the induction and on the growth of breast cancers.
... The circadian rhythm in plasma melatonin was damped in patients with an estrogen-receptorpositive breast cancer, but not in those with an estrogen-receptornegative tumor (Tamarkin et al., 1982). Rhythms in plasma melatonin, cortisol, prolactin, TSH, GH, LH and FSH were altered in patients with hormone-dependent breast cancers, but not in the case of hormone-insensitive breast tumors (Bartsch et al., 1991(Bartsch et al., , 1994. Similarly, rhythm alterations were slight in patients with early-stage prostate cancer, while major disturbances were found in patients with advanced-stage tumors (Bartsch et al., 1985(Bartsch et al., , 1994. ...
Murine and human data have indicated that tumors and tumor‐bearing hosts may exhibit nearly normal or markedly altered circadian rhythms. Amplitude damping, phase shifts, and/or period (τ) change, including appearance of ultradian rhythms (with τ < 20 hr) usually become more prominent at late stages of cancer development. The extent of rhythm alterations also varies according to tumor type, growth rate and level of differentiation. While “group chronotherapy,” i.e., administration of the same chronomodulated schedule to cancer patients, has increased chemotherapy efficacy and/or tolerability, cancer patients' individual circadian rhythms now need to be explored on a large scale, in order to estimate the incidence of cancer‐associated circadian‐system alterations and to understand the underlying mechanisms. Correlations between such alterations and patient outcome must be established in order to specify the need for individualized chronomodulated delivery schedules and/or specific rhythm‐oriented therapy, especially in patients with circadian‐system disturbance. Int. J. Cancer, 70:241–247, 1997. © 1997 Wiley‐Liss, Inc.
... 54,59 The first study evaluating the association between melatonin levels and breast cancer risk was investigated by Bartsch and co-workers. 6 It was found that the women with advanced breast cancer, when compared with healthy controls, had lower levels of urinary melatonin. Additionally, it was reported that biological assays of women with Estrogen Receptor (ER)-positive breast cancer showed an inverse relationship between ER levels and peak melatonin values. ...
Background: Chronobiological changes have been detected in various physiological functions of patients with breast cancer, suggesting dysregulation in the pineal gland and
melatonin secretion. This study aimed to assess and measure serum melatonin levels pre and postoperatively in patients who had been diagnosed for the first time with breast cancer.
Methods: A sample of first-time breast cancer patients, consisting of 45 women aged 25–65 years, was evaluated and psychometric assessment was completed using the Beck Depression
Inventory (BDI), Insomnia Severity Index (White, Weinberg et al) and the Epworth Sleepiness Scale (Cardoso, Spence et al). The Morningness-Eveningness questionnaire (MEQ) was used to
assess the chronotype. Serum melatonin levels were measured by radioimmunoassay.
Results: Morning and moderately morning chronotypes were prevalent among the sample (25%, 45.8%, respectively). The finding of a mean BDI score of 13.5±11.2 indicated that depressive symptoms were prevalent among the sample. Despite the finding that a mean of
the participants apparently had no symptoms of daytime sleepiness (the mean and standard deviations of the ESS were 7.5±4.4), scores on the ISI (a mean of 16.7±SD 7.3) indicated that insomnia symptoms were prevalent in the sample. Melatonin levels showed an inverse
relationship with insomnia severity as measured by the ISI and depression severity, as assessed by the BDI. The postoperative melatonin levels were higher than the preoperative levels. Additionally, the psychometric profile differed among various pathological types of
breast cancer according to their hormone receptor profile.
Conclusion: Serum melatonin levels correlated significantly with self-reported sleep quality and psychometric profiles of depression in the present sample of breast cancer patients. The melatonin assay, which is relatively easy to carry out, provided a convenient, objective measure of an important biological correlate of sleep quality and depression. This assay thus represented a confirmatory alternative to the self-report instruments, which may sometimes
be unreliable. Future studies should further evaluate the utility of melatonin measures in psychiatric and sleep complaints of breast cancer patients.
... Melatonin has been shown to be able to inhibit cancer development both in animal models and in vitro (Karasek & Pawlikowski, 1999;Pawlikowski, Winczyk, & Karasek, 2002). Night time serum concentration of melatonin or its metabolite, 6-hydroxymelatonin sulfate, have been observed to be lowered in several cancers such as breast cancer, endometrial cancer, prostate cancer, colorectal, lung, and stomach carcinomas (Bartsch, Bartsch, Bellmann, & Lippert, 1991;Bartsch et al., 1992;Karasek, Kowalski, & Zylinska, 2000;Khoory & Stemme, 1988). Due to its antiproliferative, antioxidant, and immunemodulatory functions, melatonin can be considered as a natural oncostatic agent (Shiu et al., 2003;J. ...
Cervical cancer is one of the most common cancers between women and is known as the third leading cause of female cancer related deaths annually. Its detection in early stages allows it to be a preventable and generally treatable disease. Increasing evidence revealed, a variety of internal and external factors are associated with initiation and progression of cervical cancer pathogenesis. Human papilloma virus infection is found as a major cause of cervical cancer. Other molecular and biochemical alterations as well as genetic and epigenetic changes are related cervical cancer progression. Current treatment options often have severe side effects and toxicities thus, new adjuvant agents having synergistic effects and ability to decrease different side effects and toxicities are needed. Melatonin is an indolamine compound secreted from the pineal gland which shows wide range anticancer activities. A large amount of studies indicated inhibitory effects of melatonin against various types of cancers. In addition, experimental evidence reports inhibitory effects of melatonin as an adjuvant therapy on cervical cancer by targeting a sequence of different molecular mechanisms. Herein, for first time, we summarized anticervical cancer effects of melatonin and its underlying molecular mechanisms.
... the important roles of melatonin in the control of reproduction in seasonally breeding animals [8], in the regulation of circadian rhythms [9], in the immune system [10,11] and as an anticancer agent [12,13], among others. In mammals, synthesis of melatonin is not restricted to the pineal gland; rather, local production of the indole has been reported in many other tissues and organs. ...
Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole’s protective actions. Melatonin’s mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.
... в 1989 г. обнаружили снижение концентрации МЛТ у пациенток с РМЖ, причем уровень МЛТ был меньше при более продвинутой стадии заболевания [37]. В 1991 г. теми же авторами установлено, что уровень МЛТ снижается только у пациенток с первичными опухолями молочной железы, в то время как при рецидиве заболевания наблюдаются нормальные значения МЛТ [38]. ...
... в 1989 г. обнаружили снижение концентрации МЛТ у пациенток с РМЖ, причем уровень МЛТ был меньше при более продвинутой стадии заболевания [37]. В 1991 г. теми же авторами установлено, что уровень МЛТ снижается только у пациенток с первичными опухолями молочной железы, в то время как при рецидиве заболевания наблюдаются нормальные значения МЛТ [38]. ...
... Indeed, in 1981, Bartsch et al. [22] published the first study demonstrating that plasma concentrations are diminished in patients with breast cancer. Since then, many studies have confirmed that patients with established breast cancer have measurably lower levels of melatonin [23,24]. ...
... Nocturnal melatonin and aMT6s levels and their circadian amplitudes were significantly depressed in the group of patients with primary breast cancer. In contrast, patients with secondary breast cancer showed nocturnal melatonin and aMT6s concentrations and amplitudes similar to benign breast disease [223] 8 young men, 7 elderly patients with benign prostatic hyperplasia and 9 patients of similar age with primary prostate cancer Serum and urine melatonin and aMT6s levels over 24 h ...
Melatonin is a natural substance ubiquitously distributed and present in almost all living species, from unicellular organisms to humans. Melatonin is synthesized not only in the pineal gland but also in most tissues in the body where it may have a cytoprotective function via paracrine or autocrine effects. Melatonin is effective in suppressing neoplastic growth in a variety of tumors. The mechanisms involved include antiproliferative effects via modulation of cell cycle, ability to induce apoptosis in cancer cells, anti-angiogenic and antimetastatic effects, anti-estrogenic activity, the capacity to decrease telomerase activity, immune modulation, and direct and indirect antioxidant effects. Besides these oncostatic properties, melatonin deserves to be considered in the treatment of cancer for two other reasons. First, because its hypnotic-chronobiotic properties, melatonin use that can allow the clinician to effectively address sleep disturbances, a major co-morbidity in cancer. Second, because melatonin’s anxiolytic and antidepressant effects, it has a possible application in two other major co-morbidities seen in cancer patients, i.e. depression and anxiety. This report summarizes the possible mechanisms involved in melatonin oncostasis and reviews what is known about the clinical application of melatonin as an adjuvant therapy in cancer patients.
... The strongest risk factors for breast cancer include age, positive family history, lifestyle, environmental and hormonal factors. 1 Additionally, melatonin hormone level and polymorphisms in its receptor genes MTNR1A and MTNR1B are recently investigated risk factors. 2,3 The pineal hormone melatonin is involved in circadian regulation and facilitation of sleep. Secretion of melatonin, the hormone of darkness, is related to the duration of darkness. ...
Abstract
Background: The main function of the pineal hormone melatonin which is mediated
via its two receptors, MTNR1A and MTNR1B, is to mediate dark signals in addition
to anti-oxidation, immune system enhancement, protection from radiation, and anti-cancer
functions. A common single nucleotide polymorphism in the MTNR1B gene is
rs#10830963, which is well known as a risk factor for type 2 diabetes mellitus. This study
intends to figure out the role of melatonin and its receptor MTNR1B gene rs#10830963
polymorphism in breast cancer incidence, diagnosis and prognosis.
Methods: This study included 43 females with breast cancer and 45 apparently normal
healthy females. Restriction fragment length polymorphism-PCR was used for amplification
and genotyping of the MTNR1B gene rs#10830963 polymorphism in whole blood. Serum
melatonin levels were measured using a ready-for-use radioimmunoassay kit.
Results: For the MTNR1B gene rs#10830963 polymorphism, we observed a
significantly higher GG genotype frequency among cases (72.1%) than controls (13.3%),
with a diagnostic sensitivity of 83.78% and specificity of 76.47%. The cases had a
frequency of 11.6% for the CC genotype and 16.3% for the CG genotype which was
significantly lower compared to controls that had a 44.4% frequency of the CC genotype
and 42.2% frequency of the CG genotype. The GG genotype had a significant association
with larger tumor volume (P=0.048). Serum melatonin levels were significantly lower
among breast cancer patients than controls. Using the ROC curve analysis, serum
melatonin showed a significant AUC (72.6%, P<0.001) with diagnostic sensitivity of
91.1% and specificity of 58% at a cut-off level of 39.5 pg/ml. Females with serum
melatonin levels ≤39.5pg/ml were at significantly increased risk for breast cancer
incidence by about 15 times more than females with levels >39.5 pg/ml.
Conclusion: The risk for breast cancer incidence increased as the serum levels of
melatonin decreased and in females homozygous for the G allele (GG genotype) of the
MTNR1B gene rs#10830963 polymorphism. The GG genotype was found to be associated
with increased breast tumor volume as a marker of a poor prognosis breast cancer.
Keywords: Breast cancer, MTNR1B gene rs#10830963SNP, Melatonin hormone, Incidence, Diagonsis, Prognosis
... Indeed, in 1981, Bartsch et al. [22] published the first study demonstrating that plasma concentrations are diminished in patients with breast cancer. Since then, many studies have confirmed that patients with established breast cancer have measurably lower levels of melatonin [23,24]. ...
Grape seed extract (GSE) from Italia, Palieri and Red Globe cultivars inhibits cell growth and induces apoptosis in Caco-2 human colon cancer cells in a dose-dependent manner. In order to investigate the mechanism(s) supporting the apoptotic process, we analysed reactive oxygen species (ROS) production, intracellular Ca2+ handling and extracellular signal-regulated kinase (ERK) activation. Upon exposure to GSE, ROS and intracellular Ca2+ levels increased in Caco-2 cells, concomitantly with ERK inactivation. As ERK activity is thought to be essential for promoting survival pathways, inhibition of this kinase is likely to play a relevant role in GSE-mediated anticancer effects. Indeed, pretreatment with N-acetyl cysteine, a ROS scavenger, reversed GSE-induced apoptosis, and promoted ERK phosphorylation. This effect was strengthened by ethylene glycol tetraacetic acid-mediated inhibition of extracellular Ca2+ influx. ROS and Ca2+ influx inhibition, in turn, increased ERK phosphorylation, and hence almost entirely suppressed GSE-mediated apoptosis. These data suggested that GSE triggers a previously unrecognised ERK-based mechanism, involving both ROS production and intracellular Ca2+ increase, eventually leading to apoptosis in cancer cells.
... By contrast, carcinogenic activities of melatonin were observed on non-hormone dependent tumors like leukemia. Experimental leukemia exhibited an increased tumor growth by melatonin administration and pinealectomy suppressed leukemic infiltrations in animal experiment [24,25]. ...
North-America and northern European countries exhibit the highest incidence rate of breast cancer, whereas women in southern regions are relatively protected. Immigrants from low cancer incidence regions to high-incidence areas might exhibit similarly higher or excessive cancer risk as compared with the inhabitants of their adoptive country. Additional cancer risk may be conferred by incongruence between their biological characteristics and foreign environment. Many studies established the racial/ethnic disparities in the risk and nature of female breast cancer in United States between African-American and Caucasian women. Mammary tumors in black women are diagnosed at earlier age, and are associated with higher rate of mortality as compared with cancers of white cases. Results of studies on these ethnic/racial differences in breast cancer incidence suggest that excessive pigmentation of dark skinned women results in a relative light-deficiency. Poor light exposure may explain the deleterious metabolic and hormonal alterations; such as insulin resistance, deficiencies of estrogen, thyroxin and vitamin-D conferring excessive cancer risk. The more northern the location of an adoptive country the higher the cancer risk for dark skinned immigrants. Recognition of the deleterious systemic effects of darkness and excessive melatonin synthesis enables cancer protection treatment for people living in light-deficient environment. Recent patents provide new methods for the prevention of hormonal and metabolic abnormities.
... Six epidemiologic studies have reported decreased melatonin levels in patients with breast cancer (68)(69)(70)(71)(72)(73), although in each of these studies, melatonin levels were measured after diagnosis, making it uncertain whether the disease itself and/or treatment might have affected melatonin levels among the cases. At least 4 studies have measured urinary melatonin levels in women before their development of breast cancer (74)(75)(76)(77). ...
Night shift work may disrupt the normal nocturnal rise in melatonin, resulting in increased breast cancer risk, possibly through increased reproductive hormone levels. We investigated whether night shift work is associated with decreased levels of urinary 6-sulfatoxymelatonin, the primary metabolite of melatonin, and increased urinary reproductive hormone levels.
Participants were 172 night shift and 151 day shift-working nurses, aged 20-49 years, with regular menstrual cycles. Urine samples were collected throughout work and sleep periods and assayed for 6-sulfatoxymelatonin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estrone conjugate (E1C).
6-Sulfatoxymelatonin levels were 62% lower and FSH and LH were 62% and 58% higher, respectively, in night shift-working women during daytime sleep than in day shift-working women during nighttime sleep (P ≤ 0.0001). Nighttime sleep on off-nights was associated with 42% lower 6-sulfatoxymelatonin levels among the night shift workers, relative to the day shift workers (P < 0.0001); no significant differences in LH or FSH were observed. 6-Sulfatoxymelatonin levels during night work were approximately 69% lower and FSH and LH were 35% and 38% higher, compared with day shift workers during nighttime sleep. No differences in E1C levels between night and day shift workers were observed. Within night shift workers, 6-sulfatoxymelatonin levels were lower and reproductive hormone levels were higher during daytime sleep and nighttime work, relative to nighttime sleep (P < 0.05).
These results indicate that night shift workers have substantially reduced 6-sulfatoxymelatonin levels during night work and daytime sleep and that levels remain low even when a night shift worker sleeps at night.
Shift work could be an important risk factor for many other cancers in addition to breast cancer.
... The pattern and levels of endogenous melatonin expression in cancer patients and tumor-bearing animal models are reportedly abnormal (Bartsch et al., 1991;Kos-Kudla et al., 2002;Cos et al., 2006). Many articles (Mocchegiani et al., 1999;Saez et al., 2005;Sainz et al., 2005;Srinivasan et al., 2008a) reported that pinealec-tomy accelerates the growth and metastasis of tumors in most experimental animal models and that exogenous melatonin inhibits the growth of tumors in human and animal models. ...
Melatonin is an important immune modulator with antitumor functions, and increased CD4(+) CD25(+) regulatory T cells (Tregs) have been observed in tumor tissues of patients and animal models with gastric cancer. However, the relationship between melatonin and Tregs remains unclear. To explore this potential connection, we performed an in vivo study by inoculating the murine foregastric carcinoma (MFC) cell line in mice and then treated them with different doses of melatonin (0, 25, 50, and 100 mg/kg, i.p.) for 1 week. The results showed that melatonin could reduce the tumor tissue and decrease Tregs numbers and Forkhead box p3 (Foxp3) expression in the tumor tissue. An in vitro study was also performed to test the effects of purified Tregs on melatonin-mediated inhibition of MFC cells. The cell cultures were divided into three groups: 1) MFC+ Tregs; 2) MFC only; and 3) MFC+CD4(+) CD25(-) T cells. After treatment with different concentrations of melatonin (0, 2, 4, 6, 8, and 10 mM) for 24 h, a dose-dependent apoptosis and cell cycle arrest at the G2/M phase was detected in melatonin-treated MFC at melatonin concentration higher than 4 mM. There were no significant differences in the rates of apoptosis and cell cycle distributions of MFC among the three groups. In conclusion, the antigastric cancer effect of melatonin is associated with downregulation of CD4(+) CD25(+) Tregs and its Foxp3 expression in the tumor tissue.
... The third study found no relationship between melatonin level and breast cancer risk (60); however, a primary concern with that study was the use of a 24-h urine sample to assess melatonin levels, which has several concerns as described by Hrushesky and Blask (61). There is evidence that melatonin levels are decreased in patients with breast cancer, although, in each of these studies, melatonin levels were measured after diagnosis; therefore, it is uncertain whether the disease itself and/or treatment might have affected melatonin levels among the cases (62)(63)(64)(65)(66)(67). Nighttime plasma melatonin levels have been reported to be lower in women with estrogen receptor-positive breast cancer than in estrogen receptornegative breast cancer, which in turn are lower than in healthy control women, and women with the lowest peak melatonin concentrations had tumors with the highest concentrations of estrogen receptors (66). ...
It would be most useful to identify a biomarker of circadian dysregulation that could be used in epidemiologic studies of the effects of circadian disruption in humans. An indicator of circulating melatonin level has been shown to be a good biomarker of circadian dysregulation and has been associated with nightshift work and exposure to light-at-night in both laboratory-based and field studies. Among other circadian markers (such as core body temperature), it remains comparatively robust in the presence of various external influences. It can be reliably measured directly and indirectly through its metabolites in urine, blood, and saliva. Urinary melatonin has been shown to be stable over time, making it useful in epidemiologic studies in which laboratory processing is not immediately available, as well as studies of cancer with long latency periods. Several studies have shown melatonin to be useful in measuring diurnal type, which is of increasing interest as it becomes more apparent that successful adaptation to shift work may be dependent on diurnal preference.
... The circadian rhythm in plasma melatonin was damped in patients with an estrogen-receptorpositive breast cancer, but not in those with an estrogen-receptornegative tumor (Tamarkin et al., 1982). Rhythms in plasma melatonin, cortisol, prolactin, TSH, GH, LH and FSH were altered in patients with hormone-dependent breast cancers, but not in the case of hormone-insensitive breast tumors (Bartsch et al., 1991(Bartsch et al., , 1994. Similarly, rhythm alterations were slight in patients with early-stage prostate cancer, while major disturbances were found in patients with advanced-stage tumors (Bartsch et al., 1985(Bartsch et al., , 1994. ...
Murine and human data have indicated that tumors and tumor-bearing hosts may exhibit nearly normal or markedly altered circadian rhythms. Amplitude damping, phase shifts, and/or period (tau) change, including appearance of ultradian rhythms (with tau < 20 hr) usually become more prominent at late stages of cancer development. The extent of rhythm alterations also varies according to tumor type, growth rate and level of differentiation. While "group chronotherapy," i.e., administration of the same chronomodulated schedule to cancer patients, has increased chemotherapy efficacy and/or tolerability, cancer patients' individual circadian rhythms now need to be explored on a large scale, in order to estimate the incidence of cancer-associated circadian-system alterations and to understand the underlying mechanisms. Correlations between such alterations and patient outcome must be established in order to specify the need for individualized chronomodulated delivery schedules and/or specific rhythm-oriented therapy, especially in patients with circadian-system disturbances.
В статье рассмотрена динамика водохозяйственных и мелиоративных
характеристик Хорезмской области с древнейших времен до современного
состояния. определен преобладающий химический состав р. Амударьи
(источник водозабора для орошаемой зоны) за отдельные периоды лет,
предложены рекомендации по улучшению мелиоративного состояния в оазисе.
Хорезмская область расположена в дельте р.
The prevalence of insomnia is high among cancer patients. However, insomnia tends to be perceived as less important problem by patients themselves as well as clinicians. In this article, cancer-specific precipitating and perpetuating factors for insomnia, development of cognitive-behavioral therapy for insomnia especially for cancer patients, and pharmacological treatment of insomnia for cancer patients will be discussed. And also, various primary sleep disorders including circadian rhythm sleep-wake disorder, sleep-related breathing disorder, restless legs syndrome, and narcolepsy or idiopathic hypersomnia will be explained in the context of cancer. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licens-es/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Insomnia is one of the most common complaints from patients with cancer and overall prevalence rate is higher than in the general population. Under the long and hard process of cancer treatment, insomnia tends to be perceived as less important problem by patients themselves as well as clinicians. However, sleeping well is a principal factor in determining quality of life and can eventually influence patients' mental health, medical condition, and treatment outcome. The cognitive-behavioral therapy for insomnia (CBT-I) is established as an effective non-pharmacological treatment which consists of sleep education, stimulus control, sleep restriction, relaxation techniques, and cognitive therapy. Especially for patients with cancer suffering from insomnia, CBT-I has been reported to reduce sleep disturbance and psychological distress and improve quality of life. This paper contains an overview of CBT-I techniques and application of CBT-I to cancer patients. We aim to customize the existing CBT-I techniques focusing on the patients' unique situations in the context of cancer trajectory.
The preliminaries of this conference have revealed that there is a fair amount of scepticism among scientists regarding possible interrelationships between the pineal gland hormone melatonin and cancer. I am sure that by the end of this conference we will be in a better position to judge for ourselves whether or not the scepticism is justified. In my view, despite the scepticism, scientists have a moral obligation towards the public, and especially the hundreds of thousands of cancer patients, to explore even the remotest possibilities to prevent, cure, or at least alleviate the suffering of this disease. On the other hand, it is mandatory not to waste public money, but to discontinue a specific branch of research once we are convinced that it is no longer promising.
Murine and human data have indicated that tumors and tumor-bearing hosts may exhibit nearly normal or markedly altered circadian rhythms. Amplitude damping, phase shifts, and/or period (τ) change, including appearance of ultradian rhythms (with τ < 20 hr) usually become more prominent at late stages of cancer development. The extent of rhythm alterations also varies according to tumor type, growth rate and level of differentiation. While “group chronotherapy,” i.e., administration of the same chronomodulated schedule to cancer patients, has increased chemotherapy efficacy and/or tolerability, cancer patients' individual circadian rhythms now need to be explored on a large scale, in order to estimate the incidence of cancer-associated circadian-system alterations and to understand the underlying mechanisms. Correlations between such alterations and patient outcome must be established in order to specify the need for individualized chronomodulated delivery schedules and/or specific rhythm-oriented therapy, especially in patients with circadian-system disturbance. Int. J. Cancer, 70:241–247, 1997.
North-America and northern European countries exhibit the highest incidence rate of breast cancer, whereas women in southern regions are relatively protected. Immigrants from low cancer incidence regions to high-incidence areas might exhibit similarly higher or excessive cancer risk as compared with the inhabitants of their adoptive country. Additional cancer risk may be conferred by incongruence between their biological characteristics and foreign environment. Many studies established the racial/ethnic disparities in the risk and nature of female breast cancer in United States between African-American and Caucasian women. Mammary tumors in black women are diagnosed at an earlier age, and are associated with a higher rate of mortality as compared with cancers of white cases. Results of the studies on these ethnic/racial differences in breast cancer incidence suggest that excessive pigmentation of dark skinned women results in a relative light-deficiency. Poor light exposure may explain the deleterious metabolic and hormonal alterations; such as insulin-resistance, deficiencies of estrogen, thyroxin and vitamin-D conferring excessive cancer risk. The more northern the location of an adoptive country, the higher the cancer risk for dark skinned immigrants. Recognition of the deleterious systemic effects of darkness and excessive melatonin synthesis enables cancer protection treatment for people living in light-deficient environment.
OBJECTIVE: To understand the effects of melatonin plus chemotherapy on the serum concentration of melatonin and the immune function of the patients with non-small cell lung cancer. METHODS : Forty-five patients confirmed were divided into two groups randomily to receive chemotherapy (NP) alone (22 cases) and chemotherapy (NP) with melatonin (23 cases), The melatonin capsules were used without interruption in every day during two chemotherapy periods. The serum concentration of melatonin, the change of cell mediated immunity and NK were detected before and after the chemotherapy. RESULTS: The circadian rhythm exsited in each group. The serum level of the melatonin at 0:00 of control group was significantly lower after two cycles of chemotherapy (t= 5.563,P=0.000), but significantly higher in the study group (t= -4.307,P = 0.000), and higher than that of the control group (t=-4.307,P = 0.000). The percentages of CD4 + and NK of the study group were significantly higher than those of the control group (t=-2.672,P = 0.012; t= -4.266,P = 0.000), while the percentage of CD8 + was significantly lower after chemotherapy (t=1.980, P=0.044). CONCLUSION: The melatonin plus chemotherapy could prevent the decline of serum concentration of melatonin and mediate the immune function of the patients with lung cancer patients.
A survey has been made of the evidence that the pineal hormone melatonin and unidentified substances affect neoplastic growth. Although a handful of scientists provided early contributions in this area, the potential role of the pineal gland in the development and growth of tumors was not acknowledged until the 1970s with the pioneering work of Vera Lapin. She and her associates concluded from experimental and clinical data that the pineal gland was involved in the development and growth of tumors. Full recognition of this potential relationship was evident with the first pineal-cancer meeting that took place in Vienna in 1977. Since that time, the majority of experimental work has focused on the relationship between the pineal indolamine melatonin and tumor growth. According to several reviews of the literature written in the interim, melatonin administration has proven to be an effective modulator of tumor growth in a variety of animal models and in human malignancy. Current work focuses on pineal effects in relation to malignant growth, stress, and the immune system. Additionally, suppressive effects of melatonin on tumor cell growth have been demonstrated in vitro. A potentially significant advancement was made by Georges Maestroni and coworkers in their suggestion that the pineal gland participates in regulating immunity through circadian melatonin production. There is growing related evidence, derived in large portion from the work of Christian and Hella Bartsch and their colleagues, that the depression of rhythmic melatonin secretion favors malignant growth by a generalized loss of synchronization of endocrine and immune functions. Although most work has focused on the relationship between melatonin and cancer, unidentified pineal compounds may play a yet undefined role in relation to neoplastic growth. Compounds extracted and purified from rat, ovine, and bovine pineal glands have been shown to inhibit cancer cell growth in a variety of in vitro systems. We have carried out related experiments that demonstrate the presence of a substance in extracts of bovine pineal glands which inhibits the growth of MCF-7 Human breast cancer cells. Sim Harto the results of other studies, the inhibitory substance appears to be a small peptide that can be purified by aqueous ethanol extraction, molecular sieve ultrafiltration and chromatography, and high-performance liquid chromatography. Determination of the chemical structure(s) of these unidentified antigrowth pineal factors could provide synthetic analogs for further testing in animal models of cancer. In conclusion, the possible relationship between the pineal gland and tumor growth suggested more than 60 years ago has become widely accepted. A significant regulatory role for the pineal hormone melatonin is suggested by its measurements in both cancer patients and experimental animal models. Although attention has focused primarily on the relationship between melatonin and malignant growth, it is also clear that other, unidentified compounds that inhibit cancer cell growth can be extracted and purified from pineal glands, but their chemical structures and modes of action are yet to be elucidated.
A review is given on the analysis of melatonin (MT) and of Its main peripheral metabolite 6-sulfatoxymelatonin (aMT6s) in patients with different types of primary unoperated cancers outside of the reproductive system, A very low production of melatonin (as estimated by the nocturnal urinary excretion of aMT6s) was found in male patients with lung or stomach cancer compared to aged-matched controls as well as in female patients with thyroid cancer. The levels of aMT6s in these women, however, did not differ from female patients with benign thyroid diseases indicating a general suppressive effect of thyroid disease on the pineal gland. A similar but opposite phenomenon was observed in male patients with primary unoperated colorectal cancer who showed an elevated production of melatonin as estimated by urinary aMT6s when compared to healthy men but not when compared to patients with colitis ulcerosa. The mechanisms involved in these phenomena are poorly understood and seem to include central as well as peripheral components. This view is supported by the finding that in spite of varying urinary aMT6s excretion measured in patients with different types of tumors, aMT6s shows comparable positive correlations with the degree of tumor cell proliferation (as estimated by the number of PCNA-immunopositive cells). Therefore the amount of aMT6s excreted (as well as the corresponding concentration of circulating MT) has to be understood as the net result of a number of different effects exerted by the tumor on the system which includes the secretion of melatonin by the pineal gland, its peripheral metabolism, and possibly also its production and release by tumor cells.
Earlier clinical studies showed that circulating melatonin is depressed in patients with primary tumors of different histological types including endocrine-dependent (mammary, endometrial, prostate) as well as endocrine-independent (lung, gastric) malignancies. The depression of circulating melatonin is most pronounced in patients with advanced localized primary tumors, where a negative correlation with the size of the tumor is found. In contrast, patients with a high risk to develop breast cancer or with early stages of prostate cancer show a very pronounced secretion of melatonin. Also a considerable number of patients with ovarian cancer exhibit a high melatonin production. The underlying mechanisms involved in the modulation of circulating melatonin in cancer patients is poorly understood and therefore studies on experimental tumor-bearing animals were performed in order to better understand this phenomenon.
This review summarizes findings relating to the concentrations of circulating melatonin as well as of the urinary excretion of 6-sulfatoxymelatonin (aMT6s, main peripheral metabolite of melatonin) in patients with different types of cancer of the reproductive system. According to these clinical studies, nocturnal circulating melatonin is diminished in patients with localized primary tumors of the mammary gland and endometrium as well as of the prostate gland. The most prominent depletions are found among patients with advanced localized primary tumors leading to a negative correlation between circulating melatonin and tumor size in patients with either mammary or prostate cancer. The phenomenon of a reduction of circulating melatonin appears to be transient since patients with recurrences show a normalization or even an elevation of melatonin. Since the surgical removal of the primary tumor does not lead to a normalization of depressed melatonin it is assumed that complex regulatory mechanisms are involved in the down-regulation of melatonin. It is unclear whether circulating melatonin is depleted in cancer patients due to a reduced production by the pineal gland or due to unknown peripheral metabolic processes. According to our investigations, an enhanced hepatic degradation to aMT6s can be ruled out in patients with mammary or prostate cancer. The depletion of circulating melatonin was found to be accompanied by neuroendocrine disturbances affecting the circadian secretion of the adenohypophyseal hormones prolactin, somatotropin and thyroid-stimulating hormone (TSH). It is conceivable that either the depletion of melatonin leads to these disturbances or that primary malignant tumor growth affects widespread systemic changes which in parallel disturb the pineal gland as well as the hypothalamo-adenohypophyseal system. As opposed to patients with mammary, endometrial or prostate cancer, extreme interindividual variations are found for unknown reasons among patients with ovarian cancer, some of them showing exceedingly highly levels of melatonin. The possible significance of the above-described findings in patients with cancers of the reproductive system is discussed with a view to achieve a better understanding of the modulation of signaling processes within the neuroimmunoendocrine network due to neoplasia.
The aim of this study was to analyze the circadian profiles of central and peripheral circulating hormones in patients with unoperated primary localized prostate cancer and to test whether any specific endocrine disturbances occur in the presence and/or during the growthf these tumors. The hormones analyzed in serum included melatonin, total testosterone, luteinizing hormone (LH), prolactin, Cortisol, total thyroxine, and thyroid stimulating hormone (TSH). Blood was collected at 4-hourly intervals over one complete 24-h cycle from 18 patients with prostate cancer, from 20 patients with unoperated benign prostatic hyperplasia (BPH) serving as age-matched controls, and from 18 young men. The single cosinor method was used for the mathematical analysis of circadian rhythmicity. The most obvious result was that the circadian amplitude of melatonin was drastically depleted in prostate cancer patients compared to those with BPH (-71%). Prostate cancer patients with primary tumors staged as T2 and higher showed extremely low melatonin levels, leading to the loss of detectable circadian rhythms. A similar trend was observed for prolactin in prostate cancer patients. A further prominent finding was that the MESOR (rhythm-adjusted 24-h mean) of TSH was clearly depleted in prostate cancer patients compared to those with BPH (-46%), showing very low values in patients with T2 and T3/T4 tumors in spite of normal total thyroxine concentrations. The circadian profiles of total testosterone, LH and Cortisol did not exhibit any marked cancer-specific changes, indicating that neither the pituitary-gonadal nor the pituitary-adrenal axis was affected by malignant growth. The observed circadian endocrine disturbances in prostate cancer patients thus show clear central endocrine disturbances. It is at present unclear whether these changes may bear any direct functional significance for the progression and prognosis of prostate cancer. It is, furthermore, unknown how these changes are generated and whether the depression of pineal melatonin secretion may be functionally involved in the observed disturbed circadian secretion of prolactin and TSH.
Melatonin is involved in many physiological functions and it plays an important role in many pathological processes as well. Melatonin has been shown to reduce the incidence of experimentally induced cancers and can significantly inhibit the growth of some human tumors, namely hormone-dependent cancers. The anticancer effects of melatonin have been observed in breast cancer, both in in vivo with models of chemically induced rat mammary tumors, and in vitro studies on human breast cancer cell lines. Melatonin acts at different physiological levels and its antitumoral properties are supported by a set of complex, different mechanisms of action, involving apoptosis activation, inhibition of proliferation, and cell differentiation.
A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded, during the la-tency phase, by a series of neuroendocrine disturbances, including attenuation of the preovulatory Luteinizing Hormone surge and Gonadotropin-Releasing Hormone release and amplification of the preovulatory 17 -Estradiol (E2) surge. Also, E2 treatment leads to a complete blunting of the Isoproterenol-induced stimulation of Melatonin secretion.In this study, we examined the hypothesis that Tamoxifen, an antagonist of E2, would stimulate the Isoproterenol-induced Mela-tonin (MT) secretion from the pineal gland, during the latency phase. Sprague-Dawley rats, 55-60 days of age, received, on the Estrous day of the Estrous cycle, a single dose of 15 mg DMBA delivered by intragastric intubation. In order to avoid possible interactions with endogenous steroids or mammary tumor-derived compounds, they were ovariectomized 5 days later and, one month later, sacrificed by decapitation at 10 a.m. Then, pineal glands were removed and placed in perifusion chambers containing Hanks 199 medium. The medium was satured with O 2 /CO 2 (95 %/5 %) and its pH was 7.4. Ten independent chambers were immersed in a water bath at 37°C. Each pineal gland received medium (flow rate : 0.16 ml/min) through a system of input lines. The fractions were collected every 10 min, and immediately frozen at –20°C until Melatonin RIA. Experiments were repeated to obtain up to five ex-perimental points for each treatment. Tamoxifen (10 -9 to 10 -7 M) was applied during the entire perifusion period (7 hours). Isoproterenol (10 -6 M) was applied for 20 min after 3 hours in perifusion. Melatonin concentrations and Areas Under the Curves were compared using two-factor ANOVA as well as parametric or nonparametric two-sample methods after test-ing sample normality. In vehicle treated rats, Tamoxifen treatment, at the concentration of 10 -9 M, leads to a non significant amplification of the Isoproterenol-induced stimulation of Melatonin secretion. In DMBA-treated rats, Tamoxifen treatment leads,starting from 10 -9 M to a dose-dependent increase (up to 400% in-crease) of the Isoproterenol-induced stimulation of Melatonin . The results suggest that in addition to the well documented beneficial effects of Tamoxifen at the mammary gland level, this E2 antagonist may also have, after DMBA treatment, an additional beneficial effect at the pineal gland level through-out the stimulation of Melatonin, which exerts an inhibitory action on the induction and on the growth of breast cancers.
There is increasing interest in the possible role of environmental factors that can alter normal endocrine function, often
referred to as “endocrine disruptors,” in the etiology of cancer. Because the release of nearly all hormones exhibits a circadian
timing patterned on approximately a 24-h cycle, agents that disrupt circadian rhythm may also alter endocrine function and
thereby the regulation of reproductive hormones (Czeisler and Klerman 1999). Of particular interest regarding breast cancer
is the potential influence of both light at night and sleep disruption on the regulation of estrogen release and levels of
circulating estrogen.
Lower urinary melatonin levels are associated with a higher risk of breast cancer in postmenopausal women. Literature for premenopausal women is scant and inconsistent.
In a prospective case-control study, we measured the concentration of 6-sulphatoxymelatonin (aMT6s) in the 12-hour overnight urine of 180 premenopausal women with incident breast cancer and 683 matched controls.
In logistic regression models, the multivariate odds ratio (OR) of invasive breast cancer for women in the highest quartile of total overnight aMT6s output compared with the lowest was 1.43 [95% confidence interval (CI), 0.83-2.45; P(trend) = 0.03]. Among current nonsmokers, no association was existent (OR, 1.00; 95% CI, 0.52-1.94; P(trend) = 0.29). We observed an OR of 0.68 between overnight urinary aMT6s level and breast cancer risk in women with invasive breast cancer diagnosed >2 years after urine collection and a significant inverse association in women with a breast cancer diagnosis >8 years after urine collection (OR, 0.17; 95% CI, 0.04-0.71; P(trend) = 0.01). There were no important variations in ORs by tumor stage or hormone receptor status of breast tumors.
Overall, we observed a positive association between aMT6s and risk of breast cancer. However, there was some evidence to suggest that this might be driven by the influence of subclinical disease on melatonin levels, with a possible inverse association among women diagnosed further from recruitment. Thus, the influence of lag time on the association between melatonin and breast cancer risk needs to be evaluated in further studies.
Accumulating studies indicate that melatonin is a natural oncostatic agent capable of mediating the influence of the psychoneuroendocrine system on cancer growth. Although there is increasing evidence to show that the pineal gland may play a role in human non-small cell lung cancer (NSCLC), there is uncertainty about circadian profiles of melatonin, its precursor tryptophan, and its major metabolite, 6-sulfatoxymelatonin (6-OH-MLT) in NSCLC patients before and after treatment with standard chemotherapy (cisplatin plus vinorelbine). The aim of this study was to investigate the concentration changes of melatonin, tryptophan, and 6-OH-MLT in NSCLC patients treated with standard chemotherapy.
We examined the circadian melatonin, tryptophan, and 6-OH-MLT rhythms in 30 patients suffering from advanced-stage NSCLC and compared them with those of 63 healthy volunteers free from neoplastic disease. Blood samples were collected at 12 noon and 12 midnight. Urine samples were collected at 7 AM: and 4 PM: . The levels of melatonin in serum and of 6-OH-MLT in urine were measured by high-performance liquid chromatography. The concentration of amino acids including tryptophan in serum was measured by amino acid analyzer.
Melatonin, tryptophan, and 6-OH-MLT concentrations were significantly lower in cancer patients, in comparison with healthy subjects. A significant inverse correlation between melatonin and tryptophan was observed. Additionally, after three cycles of standard chemotherapy, there was a tendency of melatonin, tryptophan, and 6-OH-MLT concentrations to progressively decrease in NSCLC patients.
The results of the present study indicate that the presence of NSCLC influences the metabolism of melatonin, and chemotherapy in NSCLC patients may progressively decrease the production of melatonin.
Melatonin seems to play a role in breast cancer etiology, but data addressing the association between melatonin levels and breast cancer risk in postmenopausal women is sparse.
We conducted a nested case-control study in the Nurses' Health Study cohort. First spot morning urine was collected from 18,643 cancer-free women from March 2000 through December 2002. The concentration of the major metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), was available for 357 postmenopausal women who developed incident breast cancer through May 31, 2006, along with 533 matched control subjects. We used multivariable conditional logistic regression models to investigate associations. All statistical tests were two sided.
An increased concentration of urinary aMT6s was statistically significantly associated with a lower risk of breast cancer (odds ratio for the highest versus lowest quartile of morning urinary aMT6s, 0.62; 95% confidence interval, 0.41-0.95; P(trend) = 0.004). There was no apparent modification of risk by hormone receptor status of breast tumors, age, body mass index, or smoking status.
Results from this prospective study add substantially to the growing literature that supports an inverse association between melatonin levels and breast cancer risk.
Several decades of observational data have accumulated to implicate a potential role for melatonin in cancer prevention. Experimental studies suggest that the antineoplastic action of melatonin arises through many different mechanisms, including melatonin's antioxidant, antimitotic, and antiangiogenic activity, as well as its ability to modulate the immune system and alter fat metabolism. Melatonin interacts with membrane and nuclear receptors, and may be linked to the regulation of tumor growth. Of particular relevance to breast cancer risk, melatonin may also block the estrogen receptor ERalpha and impact the enzyme aromatase, which produces estradiol. A growing number of epidemiologic studies have evaluated the relationship between night shift work as well as how varying duration of sleep affects peak melatonin secretion at night. While the studies demonstrate lower nightly melatonin levels in night workers, the evidence for an association between sleep duration and melatonin production is less clear. Similarly, both case-control and prospective cohort studies have consistently linked night shift work with breast cancer risk and, more recently, endometrial cancer - another tumor highly sensitive to estrogens. While, to date, the evidence for an association between sleep duration and breast cancer risk is less convincing, overall, there is increasing support for a potentially important link between melatonin and breast cancer risk and perhaps the risk of other tumors. As evidence increases, modifiable factors that have been shown to affect melatonin production, such as night shift work, are likely to gain increasing recognition as potential public health hazards. Additional studies are needed to delineate further the potential of melatonin in cancer prevention.
Hydroxyindole-O-methyltransferase (HIOMT) catalyzes the last step in the synthesis of the pineal hormone melatonin. In this study, an HIOMT clone was isolated from a human pineal cDNA library using synthetic oligonucleotide probes based on the bovine HIOMT sequence. The human sequence is unusual because it contains a 3' fragment (84 bp) of the LINE-1 sequence, a highly repetitive sequence in the human genome and the genome of some primates and rodents. Exclusive of this LINE-1 fragment, the human HIOMT clone is 75% and 63% homologous to bovine and avian HIOMT sequences, respectively. The deduced amino acid sequence of the human cDNA clone encodes a 41.6-kD protein. In addition, the sequence is 70% and 57% identical and 81% and 73% similar to bovine and avian HIOMT, respectively. In agreement with the results of earlier studies, it was found that vertebrate HIOMT amino acid sequences are not homologous to any other vertebrate proteins, including several methyltransferases. However, HIOMT exhibits homology with a plant O-methyltransferase and an internal 120-amino-acid region is approximately 35% identical to a region of four bacterial O-methyltransferases. The results of PCR and Southern blot analysis indicate that three species of HIOMT mRNA are typically present in the human pineal gland, only one of which contains the LINE-1 fragment. An antiserum was raised against a mixture of three synthetic peptides, corresponding to three regions of the deduced amino acid sequence of human HIOMT. This antiserum detected a single immunoreactive protein in Western blot analysis of human pineal glands. The size of the protein (approximately 42 kD) is identical to that predicted from the HIOMT clone, including the LINE-1 fragment. The human HIOMT sequence should be useful in further studies of this enzyme and will also be of special importance in evaluating the functional significance of the inclusion of a fragment of the LINE-1 in an mRNA.
The validity of melatonin as a prominent, naturally occurring oncostatic agent is examined in terms of its putative oncostatic mechanism of action, the correlation between melatonin levels and neoplastic activity, and the outcome of therapeutically administered melatonin in clinical trials. Melatonin's mechanism of action is summarized in a brief analysis of its actions at the cellular level, its antioxidative functions, and its indirect immunostimulatory effects. The difficulties of interpreting melatonin levels as a diagnostic or prognostic aid in cancer is illustrated by referral to breast cancer, the most frequently studied neoplasm in trials regarding melatonin. Trials in which melatonin was used therapeutically are reviewed, i.e., early studies using melatonin alone, trials of melatonin in combination with interleukin-2, and controlled studies comparing routine therapy to therapy in combination with melatonin. A table compiling the studies in which melatonin was used in the treatment of cancer in humans is presented according to the type of neoplasm. Melatonin's suitability in combination chemotherapy, where it augments the anticancer effect of other chemotherapeutic drugs while decreasing some of the toxic side effects, is described. Based on the evidence derived from melatonin's antiproliferative, antioxidative, and immunostimulatory mechanisms of action, from its abnormal levels in cancer patients and from clinical trials in which melatonin was administered, it is concluded that melatonin could indeed be considered a physiological anticancer substance. Further well-controlled trials should, however, be performed in order to find the link between its observed effects and the underlying mechanisms of action and to define its significance as a therapeutic oncostatic agent.
Bartsch C, Kvetnoy I, Kvetnaia T, Bartsch H, Molotkov A, Franz H, Raikhlin N, Mecke D. Nocturnal urinary 6‐sulfatoxymelatonin and proliferating cell nuclear antigen‐immunopositive tumor cells show strong positive correlations in patients with gastrointestinal and lung cancer. J. Pineal Res. 1997; 23:90–96. © Munksgaard, Copenhagen
Abstract
The hormone melatonin plays a key role in coordinating neuroendocrine signals involved in the control of biological rhythms and also appears to be involved in the regulation of cellular proliferation. In this study on patients with gastrointestinal and lung cancer the nocturnal urinary excretion of 6‐sulfatoxymelatonin (aMT6s) reflecting pineal melatonin production as well as immunohistochemically detectable proliferating cell nuclear antigen (PCNA) and melatonin were measured in corresponding tumor specimens (6 colorectal, 8 stomach, and 12 lung cancers). Strong positive correlations were detected between aMT6s and PCNA for the different types of tumors analysed (1 ≥ Rs ≥ 0.736, P < 0.01–0.0001). These findings provide support to the concept of an involvement of the pineal gland in malignancy and suggest that aMT6s‐measurements may be considered as a non‐invasive tool to estimate tumor cell proliferation. Negative correlations found between urinary aMT6s and melatonin in tumor cells (‐0.735 ≥ Rs ≥ ‐0.928, P < 0.01–0.0025) could be interpreted as an effort of the pineal gland to secrete melatonin to compensate for the decrease in the number of melatonin‐immunopositive cells within tumor tissue where it may possess important regulatory functions.
Bartsch C, Bartsch H, Karenovics A, Franz H, Peiker G, Mecke D. Nocturnal urinary 6‐sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age‐matched controls and shows negative correlation with tumor‐size. J. Pineal Res. 1997; 23:53–58. © Munksgaard, Copenhagen
Abstract
In previous studies a tumor‐size dependent decline of the circadian amplitude of serum melatonin was found in primary unoperated breast cancer patients, which was not due to changes of the hepatic metabolism of melatonin since its main peripheral metabolite, 6‐sulphatoxymelatonin (aMT6s), showed similar serum levels. The aim of the current study was to verify these previous results by measurements of the nocturnal excretion of aMT6s in urine. The determination of aMT6s was carried out by radioimmunoassay. 17 primary unoperated breast cancer (BC) patients and 34 age‐matched control patients with different types of benign gynecological diseases awaiting operation (breast diseases, n=13; ovarian diseases, n=12; and uterine diseases, n=9) were analysed. The median nocturnal urinary aMT6s excretion (22:00–6:00 hr) was significantly lower (‐48%, P = 0.033) in BC patients than in controls. Controls showed a significant negative linear regression with age (r = ‐0.419, P = 0.014). According to multivariate linear regression analysis, BC revealed no age‐dependency but a significant negative effect of increasing tumor‐size on aMT6s‐excretion (P = 0.036) was detected. These results confirm previous findings of a decreased pineal melatonin secretion in BC patients as well as an inverse relationship with tumor‐size excluding a possible distortion due to age. The mechanisms involved are unknown but indicate that BC may lead to an impaired production of pineal melatonin. The clinical relevance of these findings from therapeutic and diagnostic point of view is discussed.
Melatonin is a hormone secreted by the pineal gland in response to photoperiods and influences many important biological processes. For one, Melatonin has been shown to produce resistance to cancer and infectious diseases in aged animals. Studies in animals have demonstrated melatonin-related mechanisms of action on immunoregulation. Additionally, melatonin has been successfully used in humans, along with interleukin-2, as a treatment of solid tumors. In vivo and in vitro studies show melatonin enhances both natural and acquired immunity in animals. Despite all of this intriguing evidence, melatonin's mechanism of action on the immune system is only partially defined. It does, however, appear to act through lymphocyte receptors, and perhaps, receptors on other immune tissues, to modulate immune cells. In order to understand immunomodulation and anti-cancer effects, information on melatonin and it's interactions with other endocrine hormones are summarized.
Previous studies on human breast cancer patients showed a decline in circulating melatonin levels corresponding to primary tumor growth and an increase when relapse occurred. The aim of the current investigation was to study in an experimental model possible mechanisms involved. Inbred female F344 Fischer rats were used for serial passages derived from a chemically induced mammary adenocarcinoma. Animals with slow-growing carcinosarcomas at passage 2 showed a significant elevation of nocturnal urinary melatonin (23.00–07.00 h; +50%, p
The circulating blood cells show highly reproducible circadian rhythms. However, the factors that regulate these rhythms are not well understood. In the current study, we examined the diurnal variations of peripheral blood cells (white blood cells, neutrophils, lymphocytes), granulocyte-macrophage-colony stimulating factor (GM-CSF), and melatonin levels, and considered the role of melatonin on these rhythms in healthy volunteers and in patients with early breast cancer. Fourteen premenopausal patients with early stage breast cancer (T2, N1 tumors) and 10 premenopausal healthy volunteers were included in the study. Blood samples were taken every 4 hr for a period of 24 hr. Peripheral blood cells were counted by automated analyser and also from peripheral blood films. GM-CSF levels were measured by ELISA and melatonin levels by radioimmunoassay (RIA). Serum melatonin, cortisol, and GM-CSF levels, and peripheral blood cell counts showed significant circadian rhythms in healthy volunteers. Except for GM-CSF, these circadian rhythms were found not to be suppressed in early breast cancer patients. While there were significant correlations of serum GM-CSF and cortisol levels with peripheral blood cell counts in healthy volunteers, only lymphocyte counts were found to be significantly correlated with serum GM-CSF and cortisol levels in patients with breast cancer. Serum melatonin levels were found to be significantly correlated with lymphocyte counts in both groups. Our results suggest that peripheral blood cells show significant circadian rhythms in both healthy volunteers and in patients with stage II (T2, N1) breast cancer, and GM-CSF, cortisol, and melatonin may have a role in the regulation of peripheral blood cell counts.
The distinct melatonin rhythm with higher concentrations during the darktime was found in plasma of both control patients and patients with colorectal carcinoma. Moderate surgery did not induce any changes in plasma melatonin levels, but a pronounced increase in both the day- and nighttime melatonin concentrations was found after surgical treatment for colon cancer. The melatonin content in the tumor tissue did not differ from that in the proximal and the distal parts of the resected gut, which were without signs of malignant changes. Neither concentrations of serotonin nor 5-hydroxyindole acetic acid differed among analyzed parts of the gut. Daytime melatonin concentrations in gut tissue (314.7 +/- 87.8 pg/g of wet tissue) were more than ten times higher than the daytime levels in circulation. It was hypothesized that increased levels of this hormone in the gastrointestinal tract may play an important protective role against the development of colorectal cancer via stimulation of the immune system, protection against free radicals, and interaction with fatty acid uptake and metabolism.
A review of findings is given which relate to the levels of circulating melatonin as well as the urinary excretion of its main peripheral metabolite 6-sulphatoxymelatonin (aMT6s) in patients with different types of cancer as well as in tumor-bearing animals.
Clinical results show that circulating melatonin tends to be depressed in patients with primary tumors of different histological types including both endocrine-dependent (mammary, endometrial, prostate cancer) and endocrine-independent tumors (lung, gastric, colorectal cancer). Reduction of melatonin is most pronounced in patients with advanced localized primary tumors, such as mammary and prostate cancer where a clear negative correlation with tumor-size exists. The phenomenon of a reduction of circulating melatonin appears to be a transient one since patients with recidives show a normalization of melatonin. Surgical removal of the primary tumor does, however, not lead to normalization indicating that complex systemic changes appear to be involved in the down-regulation of melatonin. It is unclear at present, whether circulating melatonin is depleted in cancer patients due to a reduced production by the pineal gland or due to certain peripheral metabolic processes, although no evidence for an enhanced hepatic degradation to aMT6s, the main peripheral metabolite of melatonin, was found. The reduction of circulating melatonin is accompanied by neuroendocrine changes affecting the circadian secretion of the adenohypophyseal hormones prolactin, somatotropin and thyroid-stimulating hormone. In contrast to the above-described types of tumors many patients with ovarian cancer show highly elevated levels of melatonin perhaps due to the production of tissue-specific growth factors that could affect pineal melatonin secretion.
Experiments with tumor-bearing animals clearly demonstrate that nocturnal circulating melatonin is modulated due to malignant growth. Detailed investigations with chemically induced mammary tumors in rats and serial transplants derived thereof show that slow-growing and well-differentiated tumors containing epithelial cell elements (adenocar-cinomas and carcinosarcomas) lead to an enhanced production of melatonin involving activation of the rate-limiting enzyme of pineal melatonin biosynthesis (serotonin N-acetyltransferase) probably due to elevation of the sympathetic tone in response to a stimulation of the cellular immune system by malignant growth. As opposed to that nocturnal melatonin is depleted in animals with fast-growing mammary tumor transplants when myoepithelial-mesenchymal conversion leads to pure sarcomas. The reduction of melatonin appears to be due to either a reduced availability of the precursor amino acid tryptophan because of a glucocorticoid-induced activation of the hepatic enzyme tryptophan 2,3-dioxygenase or a direct peripheral degradation of melatonin via indoleamine 2,3-dioxygenase expressed in tumor and/or other tissues.
The significance of these clinical and experimental findings relating to melatonin is discussed both in terms of their practical application as a possible tumor marker and from a theoretical point of view to understand better the mechanisms involved in complex hosttumor interactions involving the neuroimmunoendocrine network.
We observed in five adenocarcinomas that norepinephrine as well as nerve fibers were absent from tumor tissue. The number of nerve fibers in normal tissue neighboring the tumor was normal. In contrast, norepinephrine concentration was decreased in normal tissue immediately surrounding tumor and increased in a stepwise fashion with the distance from tumor. Since there is evidence that some catecholamines possess antitumor activity, we suggest that depletion of catecholamines and perhaps other neurotransmitters in normal tissue neighboring a tumor may be of importance for invasion and accelerated malignant growth.
A radioimmunoassay (RIA) for urinary 6-sulphatoxymelatonin (aMT6s) using an ¹²⁵ I-aMT6s tracer is described. Iodinated aMT6s used as the label was synthesised by direct iodination of aMT6s using 1,3,4,6 tetrachloro 3,6 diphenylglycouril as the oxidant. The assay shows low cross reactivity with related compounds. Serial dilutions of 1:250 and 1:125 diluted urine gave parallel displacement curves.
Comparison of the new RIA using ¹²⁵ I-aMT6s with the RIA using ³ H-aMT6s label gave good correlation, as did comparison with a gas chromatography mass spectroscopy (GCMS) for total free and conjugated 6-hydroxymelatonin.
Urinary melatonin levels were measured in 10 postmenopausal Indian women suffering from advanced stages of breast cancer and in 9 well-matched women with non-endocrine complaints, mostly uterovaginal prolapse. Urines of each patient were collected over a period of 2-3 days in four 4-hourly intervals from 6 a.m. to 10 p.m. and one 8-hourly interval from 10 p.m. to 6 a.m. Serum LH, FSH, prolactin, estradiol and cortisol levels at 11 a.m. were determined as well as estrogen and progesterone receptors of the breast tumors. It was found that 24 hour urinary melatonin excretion in cancer patients was on the average 31% decreased as compared to the controls. This change was accompanied by a 33% increase in serum cortisol levels in the cancer patients. The melatonin excretion patterns of the cancer patients were not synchronized as compared to synchronized patterns of the controls. The number of tumors tested for steroid receptors does not yet allow to conclude if melatonin is different in patients with or without hormone-dependent tumors. The data suggest that pineal melatonin secretion may be modified in quantity as well as rhythmicity in breast cancer patients.
A simplified and rapid radioimmunoassay (RIA) for melatonin is presented. Melatonin is extracted from seru, plasma or urine and RIA is performed by using [3H]melatonin as the tracer. The standard curve covers the range 0.2--4.3 nmol/l. By increasing the sample volume the range can be extended to 0.06 nmol/l. The intra-assay variability is 7% (relative standard deviation = rsd) and the inter-assay variability is 10% (rsd). The recovery of melatonin added to calf serum is 96%. The long term variability of the assay (43 assays on aliquots of one serum sample during 6 months) is 13.5% (rsd). The serum levels in man after one oral dose of 430 mumol melatonin have been measured. The peak value, 620 nmol/l, was noted after 0.5 h and the melatonin concentration was still above the normal range at 24 h (2.1 nmol/l).
The serum levels of the pineal hormone melatonin were determined by radioimmunoassay (RIA) in 4-h intervals throughout a 24-h period in elderly men with different types of prostate tumors: benign prostatic hyperplasia (BPH, n = 13), incidental carcinoma (PCi, n = 5), and nonmetastasizing carcinoma (PC, n = 9), as well as in young men (YM, n = 10). Simultaneously, the pituitary hormones prolactin, growth hormone, luteinizing hormone and follicle-stimulating hormone were measured by RIA. All subjects were untreated and free of serious complaints, and they stayed in the same environment. The data were analyzed by the population mean-cosinor method, and linear correlation coefficients between the five hormones were calculated for each group.
Melatonin showed significant circadian rhythms in young men and patients with BPH and PCi but not in patients with PC. Twenty-four-hour mean concentration (mesor) and amplitude were significantly increased in patients with PCi as compared to patients with PC. Prolactin showed significant circadian rhythms in young men and in patients with BPH, whereas patients with PCi and PC appeared to have ultradian variations. Growth hormone did not show significant rhythms in any of the groups; the mesors were elevated in all tumor groups as compared to young men. Gonadotropin mesors were elevated in all tumor patients as compared to young men; rhythms were not detected. Carcinoma patients showed different interhormonal correlations than all other groups.
These results indicate that modulation of melatonin secretion, accompanied by changes in the pituitary hormone levels, may be related to development and growth of prostate cancer.
Serum melatonin was determined over 24 hours in 35 patients with breast cancer with either a fresh primary tumor (n = 23) or a secondary tumor (n = 12) and in 28 patients with untreated benign breast disease (controls) having a fibroadenoma (n = 10), fibrocystic mastopathy (n = 14), or other breast diseases (n = 4). Circadian rhythms existed in all groups with acrophases at 2 a.m. A 50% depression of peak and amplitude occurred in the group of patients with primary breast cancer compared with age-matched controls (P less than 0.001, P less than 0.01). The peak declined with increasing tumor size: 27% at Stage T1, 53% at T2 (P less than 0.001), and 73% at T3 (P less than 0.05). In contrast, patients with secondary breast cancer, particularly those receiving antiestrogen therapy, had a melatonin peak similar to controls. These results demonstrated a transient depression of pineal melatonin secretion in primary breast cancer and indicated a dynamic role of the pineal gland in malignancy. To investigate some endocrine effects of a depressed melatonin peak, the 24-hour rhythms of prolactin (PRL) and thyroid stimulating hormone (TSH) were determined in patients with primary breast cancer and compared with patients with secondary breast cancer. The PRL had significant circadian rhythms in both groups; but acrophases occurred at midnight in patients with secondary breast cancer, and there were unusually high concentrations at noon in patients with primary breast cancer. Circadian rhythms were not seen for TSH, but the 24-hour average secretion was depressed by 45% (P less than 0.01) in patients with primary breast cancer. The abnormal concentrations of PRL and TSH in these patients could be due to a depressed melatonin peak normally serving as a central circadian synchronizer and modulator of the secretion of adenohypophysial hormones. Additionally, a positive correlation existed between the nocturnal melatonin peak and progesterone and androgen receptor concentrations in primary tumors indicating a direct involvement of melatonin in the growth control of breast cancer.
To investigate whether melatonin (aMT) can be metabolized to N-acetyl serotonin (NAS), a low dose of deuterated aMT was administered to four normal subjects, and their urine samples were analyzed for the presence of deuterated NAS and deuterated 6-hydroxymelatonin (6-HaMT). In one set of experiments, the urine samples were subjected to column chromatography to separate the glucuronide and sulfate conjugates for independent analysis. In another, an internal standard (NAS-sulfate) was used for quantification and total conjugate analysis. Measurement was by gas chromatography-mass spectrometry, and the molecular ions of deuterated and nondeuterated NAS and 6-HaMT were monitored. Deuterated aMT was metabolized to deuterated NAS and deuterated 6-HaMT. The proportion of NAS was less in the sulfate than in the glucuronide conjugates and, overall, represented 15% of the total. Since demethylation is not a pathway that occurs with other pineal methoxyindoles, even at a much larger dose, it seems to be a significant finding with regard to aMT. Thus, it may be important to elucidate the differential metabolism of aMT at different time points and in different age groups.
An assessment of the rhythmic characteristics of melatonin secretion in man and other species requires the determination of 24-h secretion profiles. Measurement of a major excreted metabolite would allow noninvasive study of pineal function, applicable in particular to pediatric and long term circadian rhythm studies. This report describes a simple and rapid RIA for 6-hydroxymelatonin sulfate in human plasma and urine. Physiological studies revealed that both plasma and urinary levels of 6-hydroxymelatonin sulfate were closely related to plasma melatonin, and that the urinary 24-h rhythm was abolished by the beta 1-adrenergic anagonist atenolol.
The metabolism of [β-14C]melatonin has been studied in three schizophrenic and two non-schizophrenic patients. The general pattern of metabolism was found to be similar to that in rats, the major metabolic products being the sulfate and glucuronide conjugates of 6-hydroxymelatonin. Some free 6-hydroxymelatonin was also excreted together with an unidentified acidic metabolite. 6-Hydroxymelatonin and its O-sufhate conjugate were identified by comparison with the authentic compounds. The number of cases studied is too small to permit any significant comparisons to be made but there may be a somewhat higher excretion of the minor acidic metabolite by the three schizophrenic patients than by the two non-schizophrenic patients.
The effect of transplantable tumours (Yoshida Sarcoma) on pineal melatonin content was studied in Wistar rats. A negative correlation between pineal melatonin content and size of growing tumours was observed. Effects of chronic treatment with drugs interfering with n=melatonin or serotonin biosynthesis on tumour growth as well as the influence of tumour growth on pineal melatonin content were investigated. Tumour growth enhancement observed after administration of some substances producing a decrease of pineal melatonin is discussed. Pinealectomy stimulates malignant growth. This may be caused by lack of endogenous melatonin.
Plasma melatonin concentrations were determined over a period of 24 hours in 20 women with clinical stage I or II breast cancer. In ten of the patients, whose tumors were estrogen receptor positive, the nocturnal increase in plasma melatonin was much lower than that observed in eight control subjects. Women with the lowest peak concentration of melatonin had tumors with the highest concentrations of estrogen receptors. A significant correlation was found between the peak plasma melatonin concentration and the tumor estrogen receptor concentration in 19 of the patients. These data suggest that low nocturnal melatonin concentrations may indicate the presence of estrogen receptor positive breast cancer and could conceivably have etiologic significance.
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