Christian Bartsch

Stage‐dependent depression of melatonin in patients with primary breast cancer. Correlation with prolactin, thyroid stimulating hormone, and steroid receptors

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 < 0.001, P < 0.01). The peak declined with increasing tumor size: 27% at Stage T1, 53% at T2 (P < 0.001), and 73% at T3 (P < 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 < 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.

Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine of primary prostate cancer patients: Evidence for reduced pineal activity and relevance of urinary determinations

The circadian rhythms of melatonin and 6-sulfatoxymelatonin (aMT6s) were analyzed in serum and urine of young men (YM, n = 8), of elderly patients with benign prostatic hyperplasia (BPH, n = 7) and of patients of similar age with primary prostate cancer (PC, n = 9). The data expressed as concentration and in urine also as hourly excreted quantity were analyzed chronobiologically by the single cosinor method and, subsequently submitted to linear regression analyses. Circadian rhythms were detected in all cases except for the excreted quantity of melatonin. The circadian patterns of melatonin and aMT6s in serum were very similar in the different groups and regression analyses showed close correlations between both variables. MESOR and amplitude were significantly depressed in PC (40-60%) as compared to BPH and YM indicating that the depression of serum melatonin in PC is due to a reduced pineal activity and is not caused by an enhanced metabolic degradation in the liver. Acrophases of serum melatonin occurred between 01:34 and 03:26 h and of serum aMT6s between 03:58 and 04:35 h. Circadian rhythms similar to those of serum melatonin and aMT6s were found in urine, particularly for aMT6s excretion as well as melatonin concentration; the determination of both parameters in overnight urine samples closely correlated with the nocturnal peak of circulating melatonin. These results imply that it is feasible to estimate changes in pineal function of prostate cancer patients by means of non-invasive determination using urinary melatonin and aMT6s.

Seasonality of Pineal Melatonin Production in the Rat: Possible Synchronization by the Geomagnetic Field

Pineal melatonin production was estimated by means of urinary 6-sulfatoxymelatonin (aMT6s) determination in two groups of female rats for 1 year each. Seasonal changes of nocturnal aMT6s excretion were found with peak levels in summer despite constant photoperiods. We hypothesize that the horizontal component H of the geomagnetic field may act as a seasonal zeitgeber because H shows a similar seasonal rhythm, and changes in the direction and intensity of H can affect pineal activity. The observed seasonal changes of pineal melatonin production stress that despite constant environmental conditions, endocrine experiments require consideration of season, neglect of which may lead to contradictory results.

Depression of serum melatonin in patients with primary breast cancer is not due to an increased peripheral metabolism

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 < 0.01, P < 0.025). The circadian amplitudes of melatonin and 6‐sulfatoxymelatonin were also depressed by 81% (P < 0.01) and 63% (P < 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.

Nocturnal urinary 6-sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age-matched controls and shows negative correlation with tumor-size.

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.

Antitumor Activity of the Pineal Gland: Effect of Unidentified Substances versus the Effect of Melatonin

There is growing evidence that the pineal gland has antineoplastic properties which, however, can only partially be attributed to its hormone melatonin. While the in vivo tumor-inhibiting activity of melatonin is established, observations on its in vitro effects have been contradictory. The effect of this substance was investigated on six human cancer cell lines and compared to the activity of a partially purified, melatonin-free low molecular weight pineal extract (UMO5R). Melatonin showed hardly any effect but UMO5R was capable of inhibiting the growth of all the six cell lines tested. It is therefore concluded that a direct inhibiting action on tumor cells is not a general physiological role of melatonin as opposed to UMO5R. It will be worthwhile to purify the yet unidentified pineal antitumor activity since it may have a considerable therapeutic potential.

Diminished Pineal Function Coincides with Disturbed Circadian Endocrine Rhythmicity in Untreated Primary Cancer Patients

The current concept of pineal function is that its main role is to produce melatonin in a highly circadian fashion in response to neural inputs originating in the suprachiasmatic nuclei (SCN), the location of the main circadian oscillator which is tuned to environmental photoperiods by retinal signals.] The role of the melatonin signal reaching practically all organs and cells of the body due to its lipophilic nature is to convey circadian and seasonal information on the timing and duration of environmental photoperiods. The chemical signal melatonin thereby acts as a time-keeper for the different substructures of the body such as the endocrine and the immune system. On a circadian level the organism is thus tuned to phases of activity and rest or regeneration; on a circannual level adjustment of physiological functions to changing environmental conditions prevailing

Melatonin in Cancer Patients and in Tumor-Bearing Animals

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 (adenocarcinomas 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 host-tumor interactions involving the neuroimmunoendocrine network.

The Anti-tumor Activity of Pineal Melatonin and Cancer Enhancing Life Styles in Industrialized Societies

This review discusses the potential role of the anti-tumor activity of pineal melatonin for the aetiology and prevention of cancers related to life-styles in industrialized societies, e.g. frequent long-distance flights as well as chronic night shift work leading to circadian disturbances of neuroendocrine parameters including melatonin. Experimental studies show that melatonin controls not only the growth of well-differentiated cancers, but also possesses anti-carcinogenic properties. Therefore, it is plausible that disturbances of circadian melatonin rhythmicity could be functionally involved in elevated cancer risks among aircrew members and nurses frequently working on night shifts. Due to the suppression of melatonin by light it can be assumed that too much artificial light at night could, at least in part, be responsible for generally increasing rates of e.g. breast cancer in industrialized countries. It is discussed under which conditions a transient substitutional therapy with melatonin could be justified or which forms of living could help to physiologically foster melatonin secretion to optimise control over cancerous growth and development.

Effect of melatonin and pineal extracts on human ovarian and mammary tumor cells in a chemosensitivity assay.

Pinealectomy enhances tumor growth and metastatic spread in experimental animals. This effect is only in part due to melatonin since melatonin-free pineal extracts containing yet unidentified pineal substances have also shown tumor inhibiting activity. Despite numerous reports suggesting melatonin as a potential anti-cancer agent there have not been sufficient clinical trials to define the actual therapeutic potential of melatonin for the treatment of human cancers. To help fill this gap, we used a chemosensitivity assay designed to test the sensitivity of tumors from individual patients towards chemotherapeutic drugs for assessing the effect of melatonin and pineal extracts on primary human tumor cells. Primary cell cultures from seven ovarian and six mammary tumors were incubated with melatonin, the pineal extract YC05R (containing substances between 500 and 1000 daltons) and chemotherapeutic drugs. The pineal extract YC05R inhibited growth of all tumors in a dose-dependent manner. Physiological concentrations of melatonin (10(-8)-10(-10) M) inhibited the growth of one out of six mammary carcinomas in a dose-dependent manner. Primary cell cultures from three ovarian tumors were affected by melatonin in different ways, i.e., two were inhibited and one was slightly stimulated. There was no correlation between sensitivity towards melatonin and sex steroid receptor status, stage or grade of the tumor. It is concluded that, 1), melatonin may be an inhibitor of human mammary and ovarian carcinoma in individual cases and, 2), the pineal gland contains very active anti-tumor substances inhibiting both, the mammary and ovarian tumors, tested. These substances require chemical and biological identification.