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J. Neural Transmission47, 191--220 (t980)
9 by Springer-Verlag 1980
T h e R o l e of t h e P i n e a l G l a n d in Stress R. M i l i n e
Institute of Histology and Embryology, Faculty of Medicine, Novi Sad, Yugoslavia With 17 Figures Received December 17, 1979 Summary A short survey of the results of our previous research into the protective role of the pineal gland against stress is given. The neuroendocrine aspect of a chronic auditory stress and the neuroendocrine aspect of ulcer disease in man were studied. Auditory stress: hypertrophy and hyperplasia of pinealocytes, hyperplasia of the STH, FSH, LTH and TSH cells, hypertrophy of the nuclei and nucleoli of the neuroglandular cells of the supraoptic and paraventricular nuclei, pronounced hyperplasia of the cells of the reticular zone of the adrenal gland, involution of the seminal epithelium, hyperplasia of the Leydig cells. Ulcer disease: numerous glial plates, cavities and acervuli in the pineal gland, numerous granules and vacuoles in the FSH cells, large and eccentrical nuclei in the LH cells, hyperplasia of the cells of the reticular zone of the adrenal gland, presence of the seminal tubules marked by signs of involution, hyperplasia of the Leydig cells. The results obtained point to the secretion of androgens and the insufficiency of the antiandrogenic function of the pineal gland both in auditory stress and ulcer disease. The anticancerogenic effect of the pineal gland would be based on its antiandrogenic function. Key words: Pineal gland, pituitary gland, adrenal gland, testicle, auditory stress, rats, ulcer disease, man. Introduction
Effects of aggressive environmental factors upon the control mechanisms of the neuroendocrine system did represent the subject of ever more frequent studies in experimental and clinical medicine. In these studies, special consideration has been given to the pineal gland as neuroendocrine organ.
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With regard to the fact that stress is an accompanying phenomenon of everyday life and on the basis of our studies hitherto carried out, we obtained results about a functional antagonism between the pineal gland and the hypophysis, active participation of the pineal gland in the general adaptation syndrome, and its stress-induced reaction in order to protect the organism. In this paper we present a short review of our previous studies on these phenomena and give a description of our recent research aiming to clarify the role of the pineal gland in stress, especially the neuroendocrine aspect of auditory stress and the correlative role of the pineal gland and the gonads in the pathogenesis of ulcer disease. Short R e v i e w of Previous Research
Our first observations on the role of the pineal gland in stress were based upon the studies of the syndrome in the so-called "Southern-wind disease" in sheep (Miline and Janjatovi~, 1952). In this disease, an intimate correlation with the influence of environmental factors occurs such as an increase of atmospheric depression, insufficient feeding, damp, cold and sirocco. This disease is, indeed, a consequence of unsuccessful acclimatization. Before the phase of exhaustion, in the general adaptation syndrome according to Selye (1950), during this stress the pineal gland is characterized by progressive reactive changes. Our studies on the effects of light and darkness upon the histophysiological characteristics of the pineal gland in infantile rabbits and sexually mature rats revealed involutive structural changes under the influence of light and progressive changes under the influence of darkness, unlike the correlative antagonistic reaction of the supraoptic and paraventricular nuclei (Miline, 1957; Miline, 1958). In rats exposed to the effects of noise and vibrations (audiovibratory stress) and in rats affected by immobilization, we found two phases in the histophysiological reaction of the pineal gland: the first phase of involutive structural changes was followed by a phase of stimulated activity (Miline, 1957 a, b; Miline et al., 1966; Miline et al., 1968). The reaction of the pineal gland to emotional stress was studied in hares kept during 14 days aflcer the catch in cages in the presence of hunting dogs. In these animals, two phases of structural changes in the pineal gland were noticed: a phase of depressive and a phase of progressive responses of this organ as affected by fear differing from the antagonistic reaction of the supraoptic nucleus. In the second phase, hypertrophy and hyperplasia of the pinealocytes were manifest (Miline, 1957 a, b, 1960 a, b; Miline et al., 1966). In acute stress, under the influence of olfactory stimuli,
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the habenulo-epiphysial complex showed the following reactive changes: decrease in size of the nuclei of nerve cells in the medial nucleus of the habenular nuclear complex and atrophy of the pinealocytes, reflecting the functional correlation between the rhinencephalon and the pineal gland (Miline et al., 1963 a). In the irradiation syndrome, i.e. aider irradiation stress, the behaviour of the pineal gland is especially noteworthy. In rats irradiated by a onefold dose of 800 r., sacrificed during a period of 8 to 10 days, we found hypertrophy of the nuclei and nucleoli of the nerve cells of the medial nucleus of the habenular nuclear complex, hypertrophy and hyperplasia of the pinealocytes and hypertrophy of their nuclei. In rats irradiated by a sublethal dose of x-rays (600 r.), killed 8--10 weeks aider irradiation, involutive changes in the habenular nuclear complex as well as in the pineal gland were observed (Miline et al., 1963 b; MiIine et al., 1964). The pineal gland of rats, chronically exposed to the effect of low temperature (cold stress), demonstrated progressive structural changes: hypertrophy and hyperplasia of pinealocytes, polymorphism and hypertrophy of mitochondria, hypertrophy of the Golgi zone and an abundance of free ribosomes (Miline et al., 1970). Studies of the influence of solar radiation upon the pineal gland showed an opposite effect concerning its effect upon the pars intermedia of the hypophysis: the pinealocytes were decreased in size, while their nuclei were less voluminous and contained less nucleoli (Miline, 1974). An aqueous extract of the pineal gland caused inhibition of aggressiveness and crowing in co&s of Bantam breed, as well as inhibition of aggressiveness in the males of the fish Betta splendens (MiIine et al., 1959). Atter administration of an aqueous extract of the pineal gland, the animals much better resisted the harmful effect of aggression. Evidently, this extract acted as a protective against stress. In rats exposed to a lethal dose of x-rays (800 r.), reactive changes in the morphodynamics of the thyroid gland, the adrenal gland, and the lymphatic glands were very mild in comparison with the strong reactions shown in animals that were not treated with the extract. In rats treated with a sublethal dose of x-rays (600 r.), a late stressinduced reaction of the testicle was manifested by degenerative changes of the seminal epithelium and strong hyperplasia of the interstitial tissue, while in rats treated with pineal aqueous extract before and after irradiation, the structure of the seminal epithelium was preserved and hyperplasia of the interstitial tissue was very mild (Miline, 1960 a). In hares exposed to emotional stress, a favourable effect of reserpine was exerted via the habenulo-epiphysial complex, reserpine protecting the morpho-functional integrity of the complex as one of the regulators of integration and adaptation (Miline and
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~tern, 1959, 1960 d). A protective anti-stressogenic effect in the same type of stress was also exerted in these animals by substance P (~tern and Miline, 1959). In applying KJ (kalium jodatum) as the most efficient prophylactic compound against endemic goiter hitherto known, hyperplastic changes in the pineal gland were found, while a similar depressive effect (intensified diuresis) of the extract of the epiphysis and iodine upon the hypothalamic supraoptic nucleus was described (Miline, 1954). Material a n d M e t h o d s Eighty adult white male laboratory rats weighing 150--200 gm were used for the experiment. The experimental group consisted of rats exposed to noise for 8 hours (from 7 a.m. to 3 p.m.) during 14 consecutive days. The source of noise was an electric bell. The physical properties of the noise were: 86 dB (A); 89 dB (B); 91 dB (C); 94 dB (Lin); 31.5--31,000 Hz. The animals were killed by decapitation. It is known that some stressors play a role in the pathogenesis of ulcer disease, stress ulcer (Koelsch, 1976; Selye, 1950). The neuroendocrine aspect of ulcer disease was studied in 20 men aged 40--74 years. The following diagnosis were obtained: ulcus ventriculi sanguinans, ulcus ventriculi perforatum, ulcus duodeni perforatum. The material was obtained from the Institute of Pathological Anatomy. For light microscopy, organs were fixed in Bouin's and Bouin-d'Holland's fluids. Staining methods were: Florentin, G6m6ri-Bargmann, Gabe, Dominici, Alcian blue-PAS-orange G, aldehyde-thionin-PAS-orange G, Herlant (1960), Herlant and Pasteels (1967), Hurduc et aI. (1968). For histochemical and enzymological investigations, the nucleic acid reaction a~er Fenlgen, Sudan III, Sudan black and reactions on acid phosphatases, alkaline phosphatases and succinate dehydrogenase were used. For electron microscopy, tissues were fixed by immersion in 6 % glutaraldehyde in 0.2 M cacodylate buffered at pH 2.4. Postfixation was with a 1 % solution of osmic acid. This was followed by acetate dehydration and inclusion in Araldite atter Parsons. The sections were contrasted with uranyl acetate and lead citrate aider Reynolds. They were examined using an ISKRA LEM 4C electron microscope. Results
The Neuroendocrine Aspect of Auditory Stress The Pineal Gland This organ was characterized by hypertrophy and hyperplasia of the light and dark pinealocytes, grouped in smaller or bigger nodules, in the central as well as in the peripheral part of the body of the gland
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(Fig. 1). The nuclei of the pinealocytes were hypertrophied, showing deep infoldings, while the nucleoli were also hypertrophied and distributed at the periphery of the nucleus. Intensified basophilia of the cytoplasm was noticeable in the dark cells. The presence of numerous dark pinealocytes in the proximal part of the pineal gland was very conspicuous, their cell body and nucleus being smaller in size than in the control group. The distribution of the pinealocytes in the shape of a rosette or palisade was also characteristic. Vacuolation of the light pinealocytes and their disintegration into holocrine secretory products could be observed. The capillary network was much ramified and hyperemic. Sudanophilic granules were diffusely arranged throughout the gland and more numerous. The Feulgen's reaction and the activity of alkaline and acid phosphatases and succinate dehydrogenase were considerably more pronounced than in the control animals. The Pituitary Gland Somatotropic cells were more numerous, while their granular content varied very much. The Golgi zone was hypertrophied and the endoplasmic reticulum abounded in ribosomes. The reticula had taken either the shape of parallel cisternae (Fig. 2) or of concentrically distributed membranes. FSH cells were also more numerous. Many of them were hypertrophied showing frequently vacuoles in the cytoplasm. This was especially clear from the results obtained by electron microscopy. Vacuoles and cisternae of the endoplasmic reticulum were present, the Golgi zone was hypertrophied, while the secretory granules were not uniformly dense. In all the experimental animals we found hyperplasia of the LTH cells, dilation of the Golgi zone. Both the immature and mature secretory granules and the rough endoplasmic reticulum were arranged in concentric lamellae (Figs. 3, 4). Hyperplasia of the TSH cells was also found (Fig. 5). The endoplasmic reticulum abounded in dilations in the form of vacuoles and cisternae. Secretory granules varied in size and were less dense. Some mitochondria were hypertrophied. The ACTH cells were also more numerous and mostly grouped in close vicinity to the capillaries. Hypertrophy of the nuclei situated eccentrically in relation to the paracapillary cell pole was conspicuous. They were characterized by more numerous mitochondria and ribosomes. The Golgi zone was hypertrophied and showed abundant secretory granules. The pars intermedia of the hypophysis was thickened due to hyperplasia of the basophilic and dark intermediocytes. The basophilic cells were characterized by the presence of considerably more
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numerous intranuclear vacuoles. Invasion of these cells into the neural part of the hypophysis was more frequently observed in comparison with the control animals. Throughout the neural part of the hypophysis, a considerably larger amount of neurosecretion than observed in the control group was noticeable (Fig. 6). The neurosecretory fibres were characterized by two features: some had preserved their integrity, but showed more numerous Herring dilations full of elementary granules, while the others were brighter with dilations characterized by few mitochondria and elementary granules and more numerous lysosomes. The axoplasm of some neurosecretory fibres contained large vacuoles, while fibres were also observed in whose parts lamellar bodies were more numerous. The adenopituicytes ~ere characterized by hypertrophy, hyperplasia and phagocytosis, i.e. digestion of neurosecretory products in their cytoplasm (Fig. 7). Hypothalamus The neurosecretory cells of the supraoptic nuclei, separated by dilated and ramified capillaries, were more polymorphous and larger than in the control animals. Their nuclei were hypertrophied, globular, and eccentrically situated. Findings of cells showing two nuclei were characteristic. The nucleoli were hypertrophied and also eccentrically situated. The neurosecretory cells of the nuclei paraventriculares were hypertrophied, especially those of the magnocellular part of the nucleus. Their nuclei were hypertrophied as well and lying eccentrical. Vacuoles in the cytoplasm were more frequently observed than in the control animals. The Adrenal Gland In all experimental animals, groups of blastemic cells and more numerous suprarenal glands formed by the structural elements of the glomerular and fascicular zones were observed in the capsule of the adrenal. These zones were considerably thicker than in the control animals. The fascicular zone consisted of densely packed hyperplastic cells in winded rows. Among these cells the presence of large spongiocytes was conspicuous. In the reticular zone dark and light cells were present which were of a considerably larger size than in the control animals. The parts of this zone bordering on the fascicular zone were of a different size. From its inner part, numerous processes deeply invaginated the medullar substance. The cells from this zone showed abundant pigment. The medullar substance contained hypertrophied and hyperplastic medullocytes. The intramedullar symphatic 14 Journal of Neural Transmission 47/3
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nerve cells were larger showing hypertrophied and eccentrical nuclei and nucleoli. The Thyroid Gland This was formed by follicles which were smaller than in the control animals, both in the central and peripheral parts of the gland. The follicular epithelium was higher, the colloid was hypochromatic, rarefied and showed numerous resorption vacuoles. Thyreocytes with a light cytoplasm and intensely PAS-positive secretory granules prevailed. The parafollicular cells were relatively more numerous. In the interstitial tissue, mastocytes were more numerous and often situated in close vicinity to the capillaries. The Testicle In some seminal tubules of the central and peripheral parts of the testicle, very intensive involutionary changes were seen. The tubules were narrower, while their membrane was thickened and strongly PAS-positive. The seminal epithelium was very rarefied showing signs of degeneration. In some seminal tubules Sertoli cells were left only (Fig. 8). Tubules showing a lumen obliterated either by degenerated cells of the seminal epithelium or by a conjuctivo-fibrillar content were observed. Vacuolation of spermatocytes and spermatids and the genesis of teratocytes were characteristic. Of all structural elements of the seminal epithelium, the spermatogonia proved to be most resistent to the aggressive effect of noise. In all experimental animals, strong hyperplasia of the Leydig cells was clearly shown. The nuclei were of an irregular shape and showed numerous invaginations, while the nucleoli were hypertrophied. The cytoplasm, especially its perinuclear part, displayed intensified basophilia.
The Neuroendocrine Aspect of Ulcer Disease in Men The Pineal Gland The structure of the gland varied much. Most numerous were nodular or alveolar groups of cells of the glandular parenchyma separated by broad, thi& connective or fibroglia envelopes or cell streams which were very poorly vascularized (Figs. 9, 10). In the serial sections of each gland, the presence of "glial plates" was also noticed. The connective sheaths abounded in polysa&arides. Pinealocytes were either rarefied in the groups of ceils in which they
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Fig. 9. Pineal gland. Alveolar-like groups of pinealocytes; thick connective tissue and fibrogliai sheaths (Bouin, Florentin). • 500
were present being diffusely distributed, or they were dissociated due to sprouting of neuroglia elements. Their nuclei were unequal in size, while the nuclei also much varied regarding their content of chromatin. Hyperchromatic nuclei, smaller in size, prevailed. Individual cells showed GSmdri-philic and PAS-positive granules. Many intrapineal calcifications, very polymorphous and unequal in size, were observed. Besides concrements in the shape of a mulberry, some acervuli were of a globular concentrical structure, while others showed the shape of a coral or of spread liquid. Using the method of H u r d u c et al. (1968), some acervuli were totally or partly PAS-positive, while others distinctly stained dark blue or red and orange-red. On the basis of the methods applied, the analysis of the serial sections indicated that the genesis of brain sand was closely related with involutionary changes in the pinealocytes. In the nucleus and the cytoplasm the presence of globules of a variable chromophilia, which were singly or concentrically distributed, was noticed. In all the pineal glands studied cavities of unequal size were observed. Their wall consisted of connective tissue fibres and glial fibres.
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Fig. 10. Pineal gland. Large gliofibrillar pathways poorly vascularized (Bouin, Dominici). • 500
The Pituitary Gland Somatotropic cells were more numerous and their groups were surrounded by corticotropic ceils. They varied in size and were spherical or oval shaped. The larger cells contained granules of a higher density than those diffusely distributed in the cells of smaller diameters. The cells which secrete FSH, specially analysed using the method by Herlant and Pasteels (1967), were globular in shape and hypertrophied. Their cytoplasm showed abundant PAS-positive granules. The nuclei were large and peripherally distributed in the cytoplasm. Large vacuoles in the cytoplasm were an essential feature of the FSH cells. Their size was larger than that of the nuclei. The LH cells were variable in shape, well demarcated and showing hyperplasia. Their nuclei were very large and eccentrical in position. The nucleoli were also large. They were peripherally arranged or adhering to the nuclear membrane. In the sections stained following the method of Herlant and Pasteels (1967), the cytoplasm of the LH cells was light violet, containing numerous dark blue granules of different size. The L T H cells did not display any special cytophysiological feature except that they were characterized by the presence of densely packed and diffusely distributed granules. The
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thyrotropic cells were of a very irregular shape and variable size (Fig. 11), the smallest being spherical or oval, the largest polygonal. In the former, the cytoplasm was hyperchromophilic and showed densely packed granules. The presence of vacuoles in these cells was characteristic. In the hypertrophied, large, polygonal cells, the nuclei were eccentrical and spherical, while in other cells the nuclei showed a quite peripheral position having large grains of chromatin diffusely distributed. The ACTH cells were polymorphous, variable in size, and numerous. They were characterized by very small uniformly distributed granules in their cytoplasm.
Fig. 11. Pars distalis hypophyseos. Thyrotropic cells of irregular shape and size (Bouin, Alcian blue-PAS-orange G). • 500
The use of the tetra&rome method of Herlant (1960) revealed hyperplasia of the basophilic cells, to which also belong the cells by some authors beleived to secrete FSH and ACTH (Herlant, 1975). In the population of these cells, very large hypertrophied polyhedral cells characterized by large vesicular nuclei showing few chromatin and large nucleoli were conspicuous. The cytoplasm of these cells was light bluish. Some cells sporadically showed large vacuoles with rarefied erythrosinophilic small granules which were in places peripherally distributed.
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In the pars intermedia, the glandular cells were arranged in cords or dense accumulations situated between numerous larger or smaller vesicles, i.e., cysts. In some cells the cytoplasm was basophilic, granulated or homogeneous in appearance, while in others it was light. Some cells were intensely PAS-positive. In some the nuclei were eccentrical in position, spherical, with less chromatin, while in others they were hypochromatic and showing a central position. Basophilic intermediocytes deeply invaginated into the neural part of the hypophysis. One of the essential characteristics of this part of the hypophysis was its small amount of neurosecretory products, especially in humans having a perforating duodenal ulcus (Fig. 12). A prevalent presence of hyperchromatic rarefied granules in the vicinity to the capillaries as well as among the pituicytes was noticed.
Fig. 12. Pars neuralis hypophyseos. Small amount of neurosecretion (Bouin, G6mSriBargmann). X 125
The Hypothalamus The nerve cells of the supraoptic nuclei were rarefied (Fig. 13), unequal in size, less polygonal and more spherical or oval in shape. Some cells showing a wrinkled cytoplasm stained dark blue red using
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the method of G&nd'riand B~rgmann. The nuclei varied in size. The nucleoli were also of different sizes showing a variable chromophilia and position. In some cells, granules consisting of hyFochromatic products of neurosecretion were situated either in one of the cell poles or in the vicinity to the nucleus. Cells showing neurosecretory activity were especially rare in humans who died from a perforated duodenal ulcus.
Fig. 13. Nucleus supraopticus. Different sizes and variable chromophilia of the neurosecretory cells (Bouin, G&nSri-13argmann). 5<500
The cytokinetics of the nerve cells of the paraventricular nucleus was characterized by changes which agreed with the findings in the structure of the supraoptic nucleus. The Adrenal Cortex The glomerular zone was characterized by the presence of atrophic glandular cells. However, some parts of the zone showed small groups of preserved cells forming clusters and arcades. Atrophic cells were, however, much more numerous. The cell columns of the fascicular zone was narrow, parallel to each other, frequently broken up and
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Fig. 14. Adrenal gland. Involutive changes in the structure of the zona glomerulosa and zona fasciculata (Bouin, Florentin). • 125
widely separated from each other due to interstitial edema and bleeding (Fig. 14). In numerous cells of this zone signs of atrophy were observed, while groups of the cells in the process of disintegration and formation of smaller lumina could be found. The lipid content of the cells in the fascicular zone varied. The reticular zone was larger. Its ramifications entered the fascicular zone at different levels and invaginated deeply into the medulla. The cells stained mostly dark. They had a large spherical nucleus showing granules of lipofuscin (Fig. 15). The Thyroid Gland The follicles were characterized by abundant homogenously stained colloid. The follicular epithelium was isoprismatic and in some follicles partly flattened like endothelium. Parafollicular cells were present in the wall of the follicle as well as in the intrafollicular spaces.
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Fig. i5. Adrenal gland. Zona reticularis and part of the medulla (Bouin, Florentin). 5<500
Fig. 16. Testicle. Hyperpiasia of the Leydig cells (Bouin, Florentin). X 125
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The Testicle Changes were found in the structure of the seminal tubules as well as in that of the interstitial tissue. Serial sections showed that, besides seminal tubules of a normal structure and intact spermatogenic activity, also tubules were present with a distinct perturbation of the layers of the seminal epithelium. In some tubules this had become very thin and was partly devoid of its specific cellular elements. Tubules showing involution of spermatocytes and spermatids were also observed. Unlike the lumina of the seminal tubules showing a normal structure which were equal in size, the lumina of the tubules of which the structure was partly changed were narrower. They were specially characterized by the thickening of the basal membrane. The Leydig cells were hyperplastic (Figs. 16, 17) and grouped in densely packed glandulo-epithelial complexes, with well-developed capillary networks. The cells were oval or polyhedral showing very large cccentrical nuclei, containing little chromatin, which contained small granules and was peripherally situated. The nucleoli were large and frequently adhering to the nuclear membrane. Often, binuclear cells were observed. Cells containing vacuoles and cells showing hyperbasophilic perinucIear cytoplasm were numerous.
Fig. 17. Testicle. Large glandulo-epithelial complex of the Leydig cells; atrophy of the seminal tubules (Bouin, Florentin). X 125
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R. Miline: Discussion
Auditory Stress On the basis of the results described it appears that progressive cytological changes take place in the pineal gland under the influence of auditory stress. Cytophysiologically, the STH, FSH, LTH, TSH, and A C T H cells react in the same way. Stimulation of STH cell activity is a characteristic phenomenon in the general adaptation syndrome (Selye, 1950). The morphokinetics of the LTH cells also testifies to their stimulated activity and functional correlation with growth hormone, which is understandable in regard of the great similarity in molecular structure of the two hormones. The cytological aspect of the FSH and A C T H cells is not equally correlated with their target organs. The stimulated activity of the FSH cells is contrasted to the involutive, degenerative process described for the seminal epithelium, while hyperactivity of the A C T H cells goes together with the stimulated activity of the adrenal cortex. Possibly, in the former the synthesis of secretory products is stimulated only, whereas in the latter both hormone synthesis and secretion are stimulated. The reaction of the TSH cells and the thyroid gland is identical. On the basis of the results obtained in auditory stress, it would appear that the MSH production in the hypophysis is also stimulated. All stress-induced responses of the hypophysis described run parallel to the stimulated activity of the supraoptic and paraventricular nuclei. Hyperplasia of the reticular zone of the adrenal gland and of the interstitial tissue in the testicle reflects the hypersecretion of androgens. Bearing the muhipotent hormonal activity of the pineal gland in mind, specially the secretion of polypeptidic active principles and the possible presence of more different types of cells in the pineal gland than hitherto supposed, our conclusion is the following. Auditory stress, regardless of the progressive changes described, causes an insufficient antigonadotropic activity of the pineal gland, i.e., inhibition of the secretion of antiandrogenic hormone. Noise is primarily a neurogenic stressor. The results obtained indicate that the morphophysiological characteristics of the neuroendocrine system, affected by noise, reflect protection and adaptation, and not the regulation of reproductive capabilities of the organism.
Ulcer Disease On the basis of the findings described, changes in the morphokinetics of the pineal gland point to involution and suggest a decrease
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in function of this organ in ulcer disease. Also on the ground of our previous investigations, we suppose that calcification in the pineal gland is due to aggressive environmental factors. Hyperplasia of the STH cells is one of the structural characteristics of the distal part of the adenohypophysis in patients suffering from ulcer disease. Depressive changes in the pineal gland happen along with a progressive reaction of the somatotropic cells. This is in accordance with inhibition of growth hormone synthesis and secretion under the influence of melatonin (Smythe and Lazarus, 1973) and increase of the level of growth hormone in the adenohypophysis af[er epiphysectomy (Segrestaa et aI., 1975). The results of other studies testify to the correlative participation of growth hormone in the pathogenesis of ulcer disease. Administration of somatostatin, for instance, prevents the development of ulcers in rats exposed to stress (Mattes et al., 1976). The cytodynamics of the FSH cells described with special regard to their hypertrophy and vacuolation, reflects an intensified synthesis and hormone retention. Hyperplasia, viz., the kinetics of the LH cells, points to stimulation of their activity. In comparison with the well-known antiandrogenic activity of the pineal gland, these cytophysiological &aracteristics of the hypophysis indicate that in patients suffering from ulcer disease decrease in pineal function would be followed by increased activity of the FSH and LH cells. Under the influence of melatonin the blo&ade of LH, but not of FSH, happens (Motta et al., 1967), whereas the number of LH cells increases aRer pinealectomy (Girod et al., 1964), viz., the content of luteotropic hormone in the hypophysis increases (Fraschini et al., 1968). These data illustrate the role of the pineal gland in the regulation of FSH and LH cell activity. In the human material examined, the target organ of these two hormones of the hypophysis --the testes--displays essential structural changes: hyperplasia of the Leydig cells followed by thickening of the basal membrane and decreased spermatogenic activity in some seminal tubules. This dissociation in structure of the interstitial gland and the seminal epithelium, although occurring regionally, leads to an increased secretion of the hormones produced by the Leydig cells in patients suffering from ulcer. This agrees with the results of our previous studies on testosterone hypersecretion in ulcer disease (Miline, 1949). The cytodynamics of the TSH cells described and the established histophysiological characteristics of the thyroid gland agree with the manifestation of a negative feed-back in ulcer disease. On the basis of cyto-immunological research it is thought that ACTH is secreted in fl-cells, i.e., in ceils secreting FSH and, moreover, that these cells secrete LPH and MSH (Herlant, 1975). Their hyper-
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plasia and the kinetics of these cells described in the material examined testify to their hypersecretion. The investigation of the structure of the adrenal gland are in contrast. They point to an insufficient function of the first two zones of the cortex, while the reticular zone shows a hypersecretion. The dilated reticular zone and the proliferation of the interstitial tissue in the testicle suggest an increased secretion of androgenic hormones in patients suffering from ulcer. This agrees with an increased secretion of androgenic 17-ketosteroids observed in some phases of the development of ulcer disease, especially in patients having a duodenal ulcer (Alekperov, 1962) illustrating the disturbance of the homeostasis of the pituitary-adrenal axis. Results of experimental studies on the functional correlation between the pineal gland and the reticular zone of the adrenal gland point to the following. ARer pinealectomy, hyperplasia of the cells, i.e., enlargement of the reticular zone occurs (~epovi~, 1963; Deve~erski, 1965), while aiter administration of pineal extract, atrophy of this zone takes place (Miline et al., 1959). Immunohistochemical methods point to the possibility that, in man, MSH is secreted also in the distal part of the hypophysis while it is accepted that A C T H is produced in the pars intermedia (Herlant and Pasteels, 1967). The pars intermedia of the hypophysis in patients suffering from ulcer shows stimulated activity of these cells, especially in view of the invasion of intermediocytes into the neural part of the hypophysis, which might be a sign of increased intermedin secretion. This agrees with increased intermedin-like activity observed in the blood of patients suffering from ulcer (Vargas et al., 1956). An affinity for a-MSH was described earlier (Dupont et al., 1975), as well as the capability of MSH to act as a negative feed-back regulator of melatonin secretion (Kastin et al., 1972). The changes described in the structure of the two magnocellular hypothalamic neurosecretory nuclei and in the structure of the neural part of the hypophysis point to the participation of this part of the hypothalamo-hypophysial complex in the pathogenesis of ulcer disease. They are similar to the changes described by Laruelle and Reumont (1949). The aggressive characteristics of the neurosecretory cells, proving their decreased activity which is also reflected in the neural part of the hypophysis, testify to a decrease in vazopressinadiuretin secretion. This conclusion agrees with clinical observations concerning a temporary or periodical polyuria in patients suffering from ulcer. All of the results discussed concerning the neuroendocrine function in patients in the terminal phase of ulcer disease point, from the viewpoint of stressology, to a disturbance of the adaptation syndrome.
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Hypersecretion of androgens is a special feature more than the decrease in pineal and hypothalamic function. The essential feature of the neuroendocrine aspect of ulcer disease is, indeed, the unbalanced production of androgens. Insufficient antigonadotropic function of the pineal gland plays a key role in the pathogenesis of ulcer disease: the active principles of the pineal gland cannot prevent the hyperproduction of androgens. This stress-induced loss of hormonal control mechanisms is the cause of maladaptation. The carcinogenic action of androgens may explain the genesis of cancer under stress-induced conditions. Hyperandrogenism, correlated with insufficient antigonadotropic activity of the pineal gland, is the most essential physiological feature of an organism affected by aggression. From the standpoint of stressology, we are of the opinion that the favourable effect of pineal extract upon cancer, or, in reverse, the positive effect of pinealectomy upon the genesis of cancer (a subject much discussed during the Symposium) could be based upon the antiandrogenic activity of the pineal gland. From all our studies it appears that the processes occurring in the neuroendocrine system under stress are very complicated. In their determination, the hypothalamo-hypophysial and the epithalamoepiphysial complex are of special importance. These two parts of the neuroendocrine system receive a number of messages from the external environment and transform neural stimuli into hormonal responses. The pineal gland is antagonistic in function to the hypophysis exerting its anti-stressogenic effect opposing the stress-induced hyperactivity of the hypothalamo-hypophysial complex. The pineal gland, an organ of sensoneuroendocrine nature gives a hormonal response to numerous stimuli of a sensory nature such as light, sound and smell. In this way, the organ plays a role in the regulation of physiological processes in relation to the environment. The pineal gland takes an active part in the control, coordination and integration of regulatory mechanisms of the neuroendocrine system aiming at an adaptation to and a protection of the organism against aggression. We suppose that the pineal gland plays a protective role in the maintenance and fundamental stabilization of homeostasis under stress-induced conditions.
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