138 Experimental Oncology 25, 138-142, 2003 (June) ACTIVITY OF THE PINEAL GLAND, THYMUS AND HYPOPHYSIAL- ADRENAL SYSTEM IN ONCOLOGICAL PATIENTS I.F. Labunets*, Yu.A. Grinevich Institute of Oncology, Academy of Medical Sciences of Ukraine, Kyiv 03022, Ukraine ÀÊÒÈÂÍÎÑÒÜ ÝÏÈÔÈÇÀ, ÒÈÌÓÑÀ È ÃÈÏÎÔÈÇÀÐÍÎ- ÍÀÄÏÎ×Å×ÍÈÊÎÂÎÉ ÑÈÑÒÅÌÛ Ó ÁÎËÜÍÛÕ ÎÍÊÎËÎÃÈ×ÅÑÊÎÃÎ ÏÐÎÔÈËß È.Ô. Ëàáóíåö*, Þ.À. Ãðèíåâè÷ Èíñòèòóò îíêîëîãèè ÀÌÍ Óêðàèíû, Êèåâ, Óêðàèíà Melatonin, thymic serum factor (FTS), alpha-melanocytestimulating hormone (alpha-MSH) and cortisol levels in blood serum and urine of healthy subjects and patients with skin melanoma and malignant thymoma of different age groups have been studied. It has been found that in healthy 20–29 year old men the highest melatonin level was observed in winter, those of FTS, cortisol and alpha-MSH — in summer-autumn, autumn-winter and summer, respectively. In male induviduals over 30 years, the increase of melatonin level in winter was not registered, and in those over 40, the stable secretion of FTS and cortisol and decrease of alpha-MSH acrophase at spring time were observed. In healthy women under 40, melatonin level was heightened in follicular and luteal phase of cycle and that of FTS — in luteal phase. Stability of melatonin secretion and reduction of FTS content in luteal phase of cycle were typical for women over 40. The age-related disorders of indices were more pronounced upon tumor development. In men under 40 years suffering from melanoma and thymoma, circannual changes of pineal gland, thymus and hypophysial-adrenal system function were typical for healthy subjects after 40 years. In women with melanoma and thymoma under 40 years melatonin and FTS level during menstrual cycle were similar with those in healthy women over 40. In healthy subjects and oncological patients statistically significant correlation between the levels of examined hormones was found. Key Words: melatonin, thymic serum factor, alpha-melanocytestimulating hormone, cortisol, age, oncological patients. Èññëåäîâàíî ñîäåðæàíèå ìåëàòîíèíà, òèìè÷åñêîãî ñûâîðîòî÷íîãî ôàêòîðà (ÒÑÔ), àëüôà-ìåëàíîöèòñòèìóëè- ðóþùåãî ãîðìîíà (àëüôà-ÌÑÃ) è êîðòèçîëà ó ïðàêòè÷åñêè çäîðîâûõ ëþäåé è ó ïàöèåíòîâ ñ îíêîëîãè÷åñêèìè çàáîëåâàíèÿìè (ìåëàíîìîé êîæè è çëîêà÷åñòâåííîé òèìîìîé) â âîçðàñòå îò 20 äî 49 ëåò. Óñòàíîâëåíî, ÷òî ó çäîðîâûõ ìóæ÷èí â âîçðàñòå 20–29 ëåò íàèáîëåå âûñîêèé óðîâåíü ìåëàòîíèíà íàáëþäàëñÿ çèìîé, ÒÑÔ — â ëåòíå-îñåííèé ïåðèîä, êîðòèçîëà — îñåíüþ è çèìîé, àëüôà-ÌÑà — ëåòîì. Ó ìóæ÷èí ñòàðøå 30 ëåò îòñóòñòâóåò ïîâûøåíèå óðîâíÿ ìåëàòîíèíà çèìîé, à â âîçðàñòå ñòàðøå 40 ëåò îòìå÷àåòñÿ ìîíîòîííîñòü ñåêðåöèè ÒÑÔ è êîðòèçîëà, ñìåùåíèå àêðîôàçû àëüôà-ÌÑà âåñíîé. Ó çäîðîâûõ æåíùèí â âîçðàñòå äî 40 ëåò ñîäåðæàíèå ìåëàòîíèíà ïîâûøàåòñÿ â ôîëëèêóëèíîâóþ è ëþòåèíîâóþ ôàçû öèêëà, à ÒÑÔ — â ëþòåèíîâóþ. Äëÿ æåíùèí ñòàðøå 40 ëåò õàðàêòåðíà ìîíîòîííîñòü ñåêðåöèè ìåëàòîíèíà è ñíèæåíèå ñîäåðæàíèÿ ÒÑÔ â ëþòåèíîâóþ ôàçó öèêëà. Ïðè ðàçâèòèè îïóõîëè âîçðàñòíûå èçìåíåíèÿ ïîêàçàòåëåé óñèëèâàþòñÿ. Ó áîëüíûõ ìóæ÷èí â âîçðàñòå äî 40 ëåò, ñòðàäàþùèõ ìåëàíîìîé è òèìîìîé, õàðàêòåð ñåçîííûõ èçìåíåíèé ôóíêöèé ýïèôèçà, òèìóñà è ãèïîôèçàðíî-íàäïî÷å÷íèêîâîé ñèñòåìû ñîîòâåòñòâóåò òàêîâîìó ó çäîðîâûõ ìóæ÷èí ñòàðøå 40 ëåò. Ó æåíùèí äî 40 ëåò ñ ìåëàíîìîé è òèìîìîé óðîâåíü ìåëàòîíèíà è ÒÑÔ â äèíàìèêå ìåíñòðóàëüíîãî öèêëà èçìåíÿëñÿ àíàëîãè÷íî òàêîâîìó ó çäîðîâûõ æåíùèí â âîçðàñòå ñòàðøå 40 ëåò. Ó çäîðîâûõ ëþäåé è áîëüíûõ ñ îíêîïàòîëîãèåé âûÿâëåíà êîððåëÿöèîííàÿ ñâÿçü ìåæäó ñîäåðæàíèåì èññëåäîâàííûõ ãîðìîíîâ. Êëþ÷åâûå ñëîâà: ìåëàòîíèí, òèìè÷åñêèé ñûâîðîòî÷íûé ôàêòîð, àëüôà-ìåëàíîöèòñòèìóëèðóþùèé ãîðìîí, êîðòèçîë, âîçðàñò, áîëüíûå îíêîëîãè÷åñêîãî ïðîôèëÿ. A close relationship exists between the age and the cal and functional disturbances in these organs have frequency of developing malignant neoplasms in both been shown [4, 10, 11]. man and animals [1]. This phenomenon may be explai- Earlier, we have shown that in healthy subjects, an ned by age-related disorders of the functioning of en- age-related reduction in thymic serum factor (FTS) and docrine and immune systems [2–4]. During the period melatonin and increase of cortisol level occur [10, 12]. of ontogeny the activities of these systems are upon Age-related changes in the content of mentioned hor- mutual influence [5, 6], where pineal gland and thymus mones are more pronounced in cancer patients of cor- are playing one of the most important roles [7–9]. Du- responding age groups. At the same time, it was shown ring ageing and oncogenesis, significant morphologi- that the disturbance of immune and endocrine systems functions upon ageing and cancer may manifest itself Received: April 04, 2003. *Correspondence: Fax: (044) 266-01-98; not only in change of the degree of hormonal activity E-mail: [email protected] but also in the alterations of biological rhythms [13, 14]. Abbreviation used: alpha-MSH — alpha-melanocyte stimulating Primarily, this phenomenon may be associated with hormone; FTS — thymic serum factor. the disorder of functional state of the pineal gland. It Experimental Oncology 25, 138-142, 2003 (June) 139 was shown that the gland and its hormone, melatonin, The data were expressed as a mean ± standart er- play a central role in the control of the circadian orga- rors (SE). For statistical analysis, Student’s t-test was nization of various systems of organism, in particular, used. Lakin’s recomendations were used to calculate the hypophysial-adrenal and immune ones [7, 11, 15]. the correlation factor ‘η’ between variables [22]. Since circadian rhythms of the immune system have RESULTS been synchronous with the circadian rhythms of thy- mic hormones [16, 17], one can assume a possible in- Data concerning functional activity of the thymus, volvement of thymus in the regulation of the biorhyth- pineal gland, hypophysis and adrenal in healthy men mical activity of immune system via pineal gland. of different ages are presented in Table 1. FTS titer in st Interaction of pineal gland and thymus may be re- men of the 1 age group is at its maximum values in vealed also during biorhythmical activity of ovaries summer and autumn and the lowest — in winter. First (menstrual cycle). At different phases of cycle in healthy manifistations of thymic activity seasonal disturbancies women, melatonin levels and some immunological in- occur in men after after 40-ies. The highest serum dices are shown to be altered [11, 18]. Also, epithalamin, melatonin levels are found in 20–29 years old men in pineal gland’s preparation was shown to restore a cy- winter, then its concentration starts to decline progres- clic function of ovaries in aging rats and animals with sively with simultaneous changes in rhythmical pattern neoplasms [19]. of its secretion (removal of hormone acrophase to sum- Our investigation was aimed on the study of the age- mer in age group 2 and monotony of secretion in age related biorhythmical activity of the pineal gland, thy- group 3). The 20–29 years old men demonstrate clear mus and hypophysial-adrenal system in healthy sub- seasonal variation of their serum cortisol levels which jects and in oncological patients. are 1.9 times higher in autumn than in spring and sum- mer. Regular serum cortisol level gradually increases MATERIALS AND METHODS with age and is significantly higher in men after 40. We examined 236 healthy subjects (186 men and Starting from this age, seasonal variation of cortisol level 50 women) of three age groups: 1st group: 20–29 years; become less distinct. We found that alpha-MSH level 2nd group: 30–39; 3rd group: 40–49. In addition, we exa- did not differ considerably in 20–29 and 30–39 years mined 34 patients with malignant thymoma and also old men (1–2 age groups). Within these age groups, 64 skin melanoma patients with stages T1 and T2 with- the highest index was registered in summer. There was out metastases into regional lymph nodes (N0) and dis- deviation of seasonal maximum of alpha-MSH level tant organs (M0). In all patients the diagnosis was veri- from summer to spring in healthy men after 40 years fied by histological examination. The patients were 20– (age group 3). 39 years old (age groups 1–2). We examined age-associated changes of FTS ti- Thymic secretory function was evaluated in FTS ter and melatonin levels in women of different ages. (thymulin) titers (log2) [20]. Centriflo CF-50A ultrafil- The data presented in Table 2 reflects hormonal chang- ters (Amicon, USA) were used to eliminate the high es that are accompanying the menstrual cycle phases. molecular weight inhibitor of this hormone. Melatonin and FTS activity did not differ significantly in Pineal function was assessed as melatonin level in 20–29 and 30–39 years old women, therefore corres- serum, determined radioimmunologically (melatonin- ponding data were combined. We found that 20– 125 kit, “DRG”, USA) or evaluated through fluorometry 39 years old subjects (age groups 1–2) demonstrated of daily urinary excretion of 6-oxymelatonin using the a 2-fold increase of FTS titer during luteal phase of method of Dreux modified by Zubkov et al [21]. The their cycle, whereas older women showed a decrease level of 6-oxymelatonin excretion was expressed in of FTS titer during this phase. 20–39 years old sub- nmol per 24 h. jects demonstrated variation of melatonin levels with The functional activity of hypophysis and adrenal its minimum in ovulatory phase and notable increase cortex was evaluated by alpha-MSH and cortisol le- during luteal phase. In contrast, in older women we vels in blood sera, determined radioimmunologically found no variation both in the blood level of melatonin with alpha-MSH-125 kits (“DRG”, USA) and Cor- and in the rate of its excretion during these phases. teck-125 kits (“Cea-Ire-Sorin”, France, Italy). Blood The results indicate that in healthy men the corre- samples for determination of FTS, melatonin, alpha- lation exists between the content of melatonin and al- MSH and cortisol levels were taken in the morning pha-MSH (η = 0.59 + 0.22, P < 0.02), alpha-MSH and (9.00–10.00).