Activity of the Pineal Gland, Thymus and Hypophysial- Adrenal System in Oncological Patients I.F

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). Before radioimmunoassay, serum sam- cortisol (η = 0.56 ± 0.22, P < 0.02), melatonin and cor- ples were stored at –20 °C. tisol (η = 0.61 ± 0.23, P < 0.02). The correlation factors Seasonal variations of the above indices were in- between FTS and melatonin, and between FTS and vestigated in men and in women (in the last case the cortisol were 0.89 ± 0.14 (P < 0.001) and 0.63 ± 0.21 indices were studied in the dynamics of menstrual cy- (P < 0.01), respectively. The correlation between FTS cle: follicular, days 5-7, ovulatory, days 12–14, and and melatonin levels in healthy women was 0.57 ± 0.22 luteal, days 19–21 of the cycle). (P < 0.05). The blood content of hormones and levels of 6-oxy- Our data further confirms that aging is associated melatonin in the daily urine of healthy women and those not only with changes in averaged concentrations of with neoplasms were determined from February to April. thymic, pineal and pituitary-adrenal hormones but also 140 Experimental Oncology 25, 138-142, 2003 (June) it leads to the alterations in rhythmical activities of men- development further accelerated the underlying age- tioned endocrine glands. associated changes (see Table 4). Melanoma-bea- Tumor development further accelerates the pre- ring younger women (20–39 years old) showed not only existing age-associated neuroendocrine changes in- decreased FTS level in all menstrual cycle phases com- cluding alterations in some rhythmical activities. We pared the healthy control (P < 0.05) (see Table 2), but compared oncological patients of age groups under and also the lack of menstrual cycle-associated changes after 40 years. Data that reflect function of thymic, pi- in that index. In patients with malignant thymoma fluc- neal, hypophysis and adrenal glands in oncological tuations of FTS titer was typical for healthy women af- patients of 20–39 years old (age groups 1–2) are sum- ter 40 years. In women with melanoma, melatonin con- marized in Tables 3 and 4. Data presented in Table 3 tent in urine diminished in follicular phase menstrual demonstrate that melanoma patients had a decreased cycle (P < 0.05) (see Table 2). We found a stability of FTS titer in spring, summer and autumn compared to melatonin secretion during menstrual cycle in onco- healthy persons of the same age (P < 0.05) (for com- logical patients. parison see Table 1). FTS titers were stable during all It was shown that in men with melanoma the corre- seasons both in patients with melanoma and with ma- lation factor between FTS and melatonin, FTS and cor- lignant thymoma. For oncological patients, the stability tisol, melatonin and alpha-MSH was 0.83 + 0.25 of circannual melatonin content in blood and urine was (P < 0.02), 0.62 + 0.14 (P < 0.001), 0.82 + 0.16 (P < 0.02), typical, too. In patients with malignant thymoma, the respectively. In woman with melanoma the correlation η index decreased in winter compared to age control exists between melatonin and FTS levels ( = 0.57 + (P < 0.05, see Table 1). 0.21, P < 0.05). The correlation between cortisol and It should be noted that seasonal variations of alpha- FTS in patients with thymoma was 0.94 + 0.01 (P < 0.01). MSH content still could be detected in melanoma pa- Thus, the character of rhythmical hormonal chang- tients with its winter-spring maximum and subsequent es in FTS titer and melatonin levels in tumor-bearing 20–39 years old women was typical for older healthy decrease in summer. At spring and summer, the indices persons. in patients with cancer were statistically different from those in healthy person of age groups 1–2 (P < 0.05) DISCUSSION (see Table 1). The increase of alpha-MSH level in spring The investigation of the circannual interactions of and its decrease in summer in oncological patients was the pineal gland, thymus and adrenal cortex upon nor- similar with changes in healthy persons after 40 years mal ageing and pathology is very important. It was old. In patients with melanoma, cortisol content is higher shown that darkness and temperature stimulate pineal than in healthy subjects under 40 years in spring and activity in the animals and cortisosteroids are the nes- summer (P < 0.05). Cortisol level in melanoma patients sesary component of adaptive reactions of organism was stable during all seasons of year. [11, 23, 24]. New data show that the thymus may be Thus, oncological patients 20–39 years old showed involved in these reactions, too [6, 10, 25]. Glucocorti- less distinct seasonal variations of melatonin, alpha- soids are known to play a major role in the realization MSH, cortisol and FTS levels compared to healthy con- of thymic hormone activity and, in their turn, thymic trols of the same age. The character of seasonal chang- hormones themselves via a feed-back control may in- es of examined hormones in younger (age groups 1– fluence the adrenals functional state. 2) oncological patients was comparable to older persons Such interactions between the thymus and adrenal (age group 3) without cancer. cortex may take place on the hypotalamic level. Signi- Examination of endocrine status during different ficant concentrations of some thymosin peptides were phases of the menstrual cycle also revealed that tumor found in animal hypotalamus [5, 6]. The modulating in-

Table 1. FTS, melatonin, alpha-MSH and cortisol content in blood of healthy men of different age depending on the season (mean ± SE) Age groups Season Winter Spring Summer Autumn

FTS (log 2) 1 3.3 ± 0.3 (18) 4.3 ± 0.7 (10) 4.7 ± 0.4* (25) 5.2 ± 0.3* (24) 2 3.8 ± 0.5 (13) 2.5 ± 0.5*** (9) 3.7 ± 0.4 (19) 4.8 ± 0.7** (12) 3 3.4 ± 0.4 (10) 3.5 ± 0.3 (15) — 4.0 ± 0.5*** (7) Melatonin (pmol/l) 1 253.7 ± 33.2 (9) 96.5 ± 24.8* (14) 96.2 ± 21.2* (15) 132.9 ± 36.4* (11) 2 133.4 ± 45.6*** (9) 80.9 ± 17.6 (19) 158.6 ± 33.2** (11) 137.1 ± 34.3 (6) 3 134.7 ± 38.8*** (6) 44.3 ± 18.7 (7) — 83.1 ± 32.5 (4) Cortisol (nmol/l) 1 449.5 ± 61.7 (11) 303.6 ± 54.0 (7) 313.5 ± 29.5* (12) 589.3 ± 67.9** (9) 2 508.2 ± 42.3 (15) 298.3 ± 44.5* (13) 460.0 ± 180.6 (5) 509.0 ± 144.9 (5) 3 460.7 ± 92.8 (11) 438.0 ± 31.5*** (11) 415.9 ± 83.3 (7) 542.4 ± 103.5 (4) Alpha-MSH (ng/l) 1–2 118.2 ± 25.9 (13) 73.5 ± 20.4 (7) 416.1 ± 56.9*, ** (5) — 3 68.8 ± 16.3 (13) 344.7 ± 91.9*, *** (7) 231.7 ± 45.9*, *** (8) — * Statistically different from winter; P < 0.05. ** Statistically different from spring; P < 0.05. *** Statistically different from age groups 1–2 for alpha-MSH and from age group 1 for another hormones; P < 0.05. Experimental Oncology 25, 138-142, 2003 (June) 141

Table 2. FTS and melatonin levels in healthy women of different age non may be linked to age-related reduction in melato- depending on the menstrual cycle phase (mean ± SE) nin content. It was shown that β-adrenergic receptors Menstrual cycle Hor mone s Age groups in the pinealocyte membranes may decrease in num- phases 1–2 3 ber or may become unresponsive to noradrenalin upon Follicular FTS (log2) 4.6 ± 0.7 (12) 5.5 ± 2.0 (4) Melatonin in: 130.6 ± 32.9 (6) 163.4 ± 45.2 (4) the ageing, as has been described in rodents [14]. Be- serum (pmol/l) sides, the activity of N-acethyltransferase, key enzyme urine (nmol/24 h) 63.3±5.0* (11) 47.2 ± 11.2 (3) responsible for the synthesis of melatonin, decreases Ovulatory FTS (log2 ) 4.7 ± 0.6 (10) 4.8 ± 1.1 (6) Melatonin in: 156.5 ± 46.0 (6) 92.5 ± 29.5 (4) dramatically in the pineal gland of old rats in parallell serum (pmol/l) with the decline of rat serum melatonin, regardless of urine (nmol/24 h) 40.8 ± 7.1 (10) 48.6 ± 18.3 (4) the circadian stage. The age-related changes were Luteal FTS (log2) 5.5 ± 0.5 (12) 3.2 ± 0.7** (6) Melatonin in: 480.7 ± 202.9 (5) 178.0 ± 68.4 (5) found in the interactions between the pineal gland and serum (pmol/l) suprachiasmatic nucleus of hypothalamus where the urine (nmol/24 h) 66.2 ± 8.0* (5) 43.2 ± 11.4 (5) * Statistically different from ovulatory phase; P < 0.05. receptors for melatonin are present [14, 15]. It was es- ** Statistically different from age groups 1–2; P < 0.05. tablished that pineal gland regulates functions of many Table 3. FTS, melatonin, alpha-MSH and cortisol content in male patients* with organism’s systems including hypotalamic-hypophy- melanoma and malignant thymoma depending on the season (mean ± SE) sial-adrenal system through rhythmic secretion of me- Hormones Season latonin [15, 27]. This hormone may modify endocrine Winter Spring Summer Autumn feedback sensitivities of the hypotalamus to peripheral Patients with melanoma hormone inputs [19]. FTS (log2) 3.0 ± 0.7 (11) 2.2 ± 0.6 (12) 2.0 ± 0.4 (10) 2.3 ± 0.8 (10) Melatonin in 58.6 ± 15.4 43.0 ± 9.9 62.3 ± 18.8 51.0 ± 14.5 The maitenance of the pineal gland’s function is of urine (nmol/24 h) importance not only for organism’s circadian rhythms but alpha-MSH (ng/l) 194.4 ± 45.2 175.2 ± 39.5 148.1 ± 20.1 — Cortisol (nmol/l) 577.0 ± 60.8 656.9 ± 54.9 526.1 ± 58.9 671.3 ± 58.4 also for the internal rhythms which are not synchronous Patients with malignant thymoma with environmental cycles, for example, the menstrual FTS (log2) 3.3 ± 0.9 (7) 3.8 ± 0.6 (7) — 4.0 ± 1.5 (7) cycle. It was shown that changes in the secretion of Melatonin 103.2 ± 45.4 143.6 ± 43.3 116.1 ± 29.7 melatonin, i.e., higher levels during the luteal phase and in serum (pmol/l) * Patients of 20–39 years old (age groups 1–2). lower values preceding and at the time of ovulation act Table 4. FTS and melatonin content in women* with melanoma and as a modulator of ovarian cycliticy in the human [11]. malignant thymoma on the menstrual cycle phase depending (mean ± SE) Such changes lead to the release of ovulatory hormones Menstrual cycle Hor mone s Patients with and subsequent ovulation. At the same time, the thy- phases melanoma malignant mosin was shown to stimulate the release of the lutein- thymoma Follicular FTS (log 2) 2.2 ± 0.6 (6) 5.2 ± 0.9 (5) izing hormone-releasing hormone by the hypothalamus, Melatonin in: — 467.2 ± 203.3 (4) and the feed-back link exists between thymus and ova- serum (pmol/l) ries [6, 28]. These findings and our data support the pos- urine (nmol/24 h) 44.5 ± 5.5 (7) — Ovulatory FTS (log 2) 2.0 ± 0.9 (6) 4.3 ± 1.3 (4) sibility of involvement of thymus in the regulation of ova- Melatonin in urine 41.5 ± 10.1 (5) — rian cyclicity by the pineal gland. Therefore age-related (nmol /24 h) changes in the secretion of melatonin and FTS may be Luteal FTS (log 2) 1.4 ± 0.4 (9) 3.3 ± 0.1** (4) Melatonin in: — 107.5 ± 56.3 (4) connected in the women after 40 years. serum (pmol/l) From the point of view of oncology, the frequency urine (nmol/24 h) 44.1 ± 10.0 (6) — of developing malignant neoplasms increases after * Patients of 20–39 years old (age groups 1–2). ** Statistically different from follicular phase; P < 0.05. 40 years. Among the age-related disorders, the bio- rhythmical activity of the adaptive and reproductive sys- fluence of thymic hormone on the adrenocorticotrophic tems and primarily of the pineal gland may play an im- activity of the hypophysis has been demonstrated [25]. portant role. The inhibitory influence of pineal secreto- The importance of the hypotalamic-hypophysial sys- ry products on proliferation of normal and neoplastic tem, in particular alpha-MSH, in the regulation of adreno- cells was shown [1, 19]. cortical activity is generally accepted [26]. Considering Our clinical studies have demonstrated that age- the possibility of a two-way interaction of thymus and related disorders of rhythms of endocrine system are adrenal cortex and our data about the character of cir- more pronounced in patients with neoplasms than in cannual changes in the FTS, alpha-MSH and cortisol healthy subjects. It was found that in oncological pa- levels in healthy subjects in age group 1, we can sug- tients under 40 the dynamics of seasonal variations of gest that the changes in the secretory function of these the levels of studied hormones during menstrual cycle glands might reciprocally influence each other. were similar to those in healthy subjects over 40 thus During ageing in men (especially after 40 years), pointing to the acceleration of age-related changes in an excess of glucocortisoids and deficiency of thymic the function of the endocrine glands upon tumor de- hormones develops [12] as well as the signs of a dis- velopment. Therefore, the influence aimed on normali- accord of the rhythmical activity of the thymus and hy- zation of age-related biorhythmical dysfunction of en- pophysial-adrenal system characterized by the loss of docrine glands may provide an effective approach to fluctuation (seasonal FTS and cortisol levels) and dis- prevention and treatment of malignant neoplasms. The placement of acrophase (alpha-MSH level to spring). use of specific drugs to alter the period and/or the phase One of the most important reasons of this phenome- of circadian rhythms may be useful, in particular, me- 142 Experimental Oncology 25, 138-142, 2003 (June) latonin that is able to restore the rhythmical disturbances endocrine organs. Reiter RJ, eds. Vienna: Springer, 1989: of some metabolic indices in older patients [14]. We 96–149. have shown that pineal activation with the use of epi- 16. Mc Gillis JP, Hall NR, Goldstein AL. 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