Physiology of the pineal gland (epiphysis)

The pineal gland, or epiphysis, is the outgrowth of the roof of the third ventricle of the brain. It is covered with a connective tissue capsule, from which the strands separating the organ into lobes go inside. Lobules of the parenchyma contain pinealocytes and glial cells. Among the pinealocytes, larger, lighter, and smaller in size dark cells are distinguished. The peculiarity of the vessels of the epiphysis is, apparently, the absence of close contacts between endothelial cells, whereby the blood-brain barrier in this organ is untenable. The main difference between the epiphysis of mammals and the corresponding organ of the lower species is the absence of sensitive photoreceptor cells in it. Most of the nerves of the epiphysis are represented by the fibers of the cells of the upper cervical sympathetic ganglia. Nerve endings form networks around the pinealocytes. The processes of the latter contact the blood vessels and contain secretory granules. Epiphysis is especially noticeable at a young age. By the period of puberty, its size usually decreases, and later in it calcium and magnesium salts are deposited. Such calcification often allows you to see the epiphysis well on the radiographs of the skull. The mass of the pineal gland in an adult is about 120 mg.

The activity of the epiphysis depends on the periodicity of the illumination. In the light, synthetic and secretory processes in it are inhibited, and in the dark intensify. Light pulses are perceived by the retina receptors and enter the centers of regulation of the sympathetic nervous system of the brain and spinal cord and then to the upper cervical sympathetic ganglia, which give rise to the innervation of the pineal gland. In the dark, inhibitory neural influences disappear, and the activity of the epiphysis increases. Removal of the upper cervical sympathetic ganglia leads to the disappearance of the rhythm of activity of the intracellular enzymes of the epiphysis, taking part in the synthesis of its hormones. Norepinephrine-containing nerve endings through cellular beta receptors increase the activity of these enzymes. This circumstance seems to contradict the data on the inhibitory effect of stimulation of the sympathetic nerves on the synthesis and secretion of melatonin. However, on the one hand, it was shown that in the conditions of illumination the content of serotonin in iron decreases, and on the other hand, the role of cholinergic fibers in the regulation of the oxyindole-O-methyltransferase (OIOMT) activity of the epiphysis is also revealed.

Cholinergic regulation of the activity of the epiphysis is confirmed by the presence in this organ of acetylcholinesterase. The source of cholinergic fibers is also the upper cervical ganglia.

The epiphysis produces mainly indole-N-acetyl-5-methoxytryptamine (melatonin). Unlike its predecessor, serotonin, this substance is synthesized, apparently, exclusively in the pineal gland. Therefore, its concentration in the tissue, as well as the activity of the OIOMT, serve as indicators of the functional state of the epiphysis. Like other O-methyltransferases, OIOMT uses S-adenosylmethionine as a methyl group donor. Substrates of methylation in the epiphysis can serve as both serotonin and other 5-hydroxyindoles, but N-acetylserotonin is more (20 times) the preferred substrate of this reaction. This means that during the synthesis of melatonin, N-acetylation precedes O-methylation. The first step in the biosynthesis of melatonin is the conversion of the tryptophan amino acid under the influence of tryptophan hydroxylase to 5-hydroxytryptophan. With the help of decarboxylase of aromatic amino acids, serotonin is formed from this compound, part of which is acetylated, converting to N-acetylserotonin. The final stage of the synthesis of melatonin (conversion of N-acetylserotonin under the action of OIOMT), as already noted, is specific for the epiphysis. Unacetylated serotonin is deaminated by monoamine oxidase and is converted to 5-hydroxyindoleacetic acid and 5-hydroxytryptophol.

A significant amount of serotonin also enters the nerve endings, where it is captured by granules, which prevent the enzymatic degradation of this monoamine.

It is believed that the synthesis of serotonin occurs in the light pinealocytes and is controlled by noradrenergic neurons. Cholinergic parasympathetic fibers regulate the release of serotonin from light cells and, thereby, its accessibility to dark pinealocytes, in which noradrenergic modulation of the formation and secretion of melatonin also takes place.

There are data on the production of the epiphysis, not only indoles, but also substances of a polypeptide nature, and, according to a number of researchers, they are the true hormones of the pineal gland. Thus, an antigonadotropically active peptide (or mixture of peptides) with a molecular weight of 1000-3000 daltons is isolated from it. Other authors postulate the hormonal role of arginine-vasotocin isolated from the epiphysis. Still others - received from the epiphysis two peptide compounds, one of which stimulated, and the other inhibited the secretion of gonadotropins by the culture of the pituitary cells.

In addition to ambiguities about the true nature of the hormone (hormones) of the pineal gland, there are disagreements about the way it enters the body: into the bloodstream or into the cerebrospinal fluid. However, most of the evidence suggests that, like other endocrine glands, the epiphysis secretes its hormones into the bloodstream. The problem of central or peripheral action of epiphyseal hormones is closely connected with this problem. In experiments on animals (mainly on hamsters) it was established that the epiphyseal regulation of the reproductive function is due to the influence of the pineal gland on the hypothalamic-pituitary system, and not directly on the sex glands. Moreover, the introduction of melatonin in the third ventricle of the brain reduced levels of luteinizing (LH) and follicle-stimulating (FSH) hormones and increased prolactin levels in the blood, whereas melatonin infusion into the portal vessels of the pituitary was not accompanied by a change in the secretion of gonadotropins. One of the places of application of the action of melatonin in the brain is the mid elevation of the hypothalamus, where liberins and statins are produced that regulate the activity of the anterior lobe of the pituitary gland. However, it remains unclear whether the production of these substances under the influence of melatonin itself, or it modulates the activity of mono-aminergic neurons, and thus participates in the regulation of the production of releasing factors. It should be emphasized that the central effects of the hormones of the epiphysis do not prove their direct secretion into the cerebrospinal fluid, since they can get there and from the blood. In addition, there are data on the effect of melatonin and at the level of the testes (where this substance inhibits the formation of androgens) and other peripheral endocrine glands (for example, weakening the influence of TSH on the synthesis of thyroxine in the thyroid gland). Prolonged introduction of melatonin into the blood reduces the testes mass and testosterone level in the serum even in hypophysectomized animals. Experiments have also shown that bezmelaninic extract of the epiphysis blocks the effect of gonadotropins on the weight of the ovaries in hypophysectomized rats.

Thus, biologically active compounds produced by this gland apparently have not only a central but also a peripheral action.

Among the many diverse effects of these compounds, their influence on the secretion of the gonadotropins of the pituitary gland attracts the greatest attention. Data on the violation of puberty in epiphyseal tumors were the first indication of its endocrine role. Such tumors can be accompanied by both acceleration and retardation of puberty, which is associated with the different nature of the outgrowths of parenchymal and non-parenchymatous cells of the epiphysis of tumors. The main evidence of the antigonadotropic effect of the hormones of the pineal gland was obtained on animals (hamsters). In the dark (i.e., under the conditions of activation of the epiphysis function), the animals show a pronounced involution of the genital organs and a decrease in the level of LH in the blood. In epiphysectomized individuals or in conditions of cutting the nerves of the epiphysis, darkness does not have such an effect. It is believed that the antigonadotropic substance of the epiphysis prevents the release of lyuliberin or its action on the pituitary gland. Similar, albeit less precise, data are obtained in rats whose darkness somewhat delays puberty, and the removal of the epiphysis leads to an increase in the levels of LH and FSH in the blood. Particularly distinctly antigonadotropic effect of the epiphysis is observed in animals with a disturbed function of the hypothalamic-pituitary-gonadal system by the introduction of sex steroids in the early postnatal period.

Epiphysectomy in such rats restores sexual development. Antigonadotropic effects of the pineal gland and its hormones are also enhanced in an anosmia and fasting condition.

Inhibitory effect on the secretion of LH and FSH has not only melatonin, but its derivatives - 5-methoxytryptophol and 5-oxytryptophol, as well as serotonin. As already noted, the inadequately identified polypeptide products of the epiphysis also have the ability to influence the secretion of gonadotropins in vitro and in vivo. One such product (with a molecular weight of 500-1000 daltons) was 60-70 times more active than melatonin in relation to blockade of hypertrophy of the remaining ovary in unilateral ovariectomized mice. Another fraction of epiphysis peptides, on the contrary, produced a gonadotropin effect.

Removal of the epiphysis in immature rats leads to an increase in the prolactin content in the pituitary gland with a simultaneous decrease in its level in the blood. Analogous shifts take place in animals kept in constant light, while the opposite shifts occur in rats in the dark. It is believed that the pineal gland secretes a substance that interferes with the influence of the prolactin-inhibiting factor (UIF) of the hypothalamus on the synthesis and secretion of prolactin in the pituitary gland, as a result of which the hormone content in this gland decreases. Epiphysectomy causes opposite changes. The active substance of the epiphysis in this case is probably melatonin, since its injection into the third ventricle of the brain transiently increased the level of prolactin in the blood.

In the conditions of a constant absence of light, the growth of animals slows down and the content of growth hormone in the pituitary gland decreases significantly. Epiphysectomy removes the effect of darkness and sometimes, in itself, accelerates growth. The introduction of epiphysis extracts reduces the stimulating growth effect of pituitary medications. At the same time, melatonin does not affect the growth rate of animals. Perhaps, some other epiphyseal factor (factors) inhibits the synthesis and release of somatoliberin or stimulates the production of somatostatin.

In experiments it was shown that the influence of the epiphysis on the somatotropic function of the pituitary gland is not mediated by a deficiency of androgens or thyroid hormones.

In epiphysectomized rats, the secretion of corticosterone increases transiently, although the stress response of the adrenal glands is significantly weakened after removal of the epiphysis. Secretion of corticosterone increases in conditions of constant illumination, which, as is known, inhibits the activity of the pineal gland. There is evidence that the removal of the epiphysis weakens the compensatory hypertrophy of the remaining adrenal gland after unilateral adrenalectomy and disrupts the circadian rhythm of the secretion of glucocorticoids. This indicates the importance of the epiphysis for the adrenocorticotropic function of the anterior lobe of the pituitary gland, which is confirmed by a change in the production of ACTH by the tissue of the pituitary gland removed from the epiphysectomized animals. Regarding the active beginning of the epiphysis, which affects the adrenocorticotropic activity of the pituitary gland, there is no consensus in the literature.

Removal of the epiphysis increases the content of melanocyte-stimulating hormone (MSH) in the pituitary gland, whereas the introduction of melatonin in the cerebral palsy of the cerebral ventricle reduces its content. The level of the latter in the pituitary gland of rats living in the light increases, and the introduction of melatonin blocks this effect. It is believed that melatonin stimulates hypothalamic production of melanotropin inhibiting factor MYTH.

The influence of the epiphysis and its hormones on other tropic functions of the pituitary gland is less studied. Changes in the activity of peripheral endocrine glands can occur due to the direct action of epiphyseal factors. Thus, removal of the epiphysis leads to a certain increase in the mass of the thyroid gland, even in the absence of the pituitary gland. The rate of secretion of thyroid hormones increases very little and briefly. However, according to other data, the epiphysis has an inhibitory effect on the synthesis and secretion of TSH in immature animals.

In most experiments subcutaneous, intraperitoneal, intravenous and even intraventricular administration of melatonin resulted in a decrease in iodine-concentrating function of the thyroid gland.

The epiphysis of the adrenal glands, without affecting the state of the bundle and reticular zones of the cortex, almost doubled the size of the glomerular zone, which indicates the direct action of the epiphysis products on the cells that produce mineralocorticoids. Moreover, the substance (1-meth-hydroxy-1,2,3,4-tetrahydro-beta-carboline), stimulating the secretion of aldosterone and therefore called adrenoglomerulotropin, was isolated from the epiphysis. However, soon data were obtained that denied the physiological role of this compound and even questioning the very existence of a specific adreno-glomerulotrophic factor of the epiphysis.

There are reports that removal of the epiphysis reduces the functional activity of the parathyroid glands. There are also opposite observations. The results of the study of the influence of the epiphysis on the endocrine function of the pancreas are mostly negative.

At present, there are still many unresolved issues concerning, in particular, the nature of the compounds produced by this gland. The least doubt is the influence of the epiphysis on the secretion of tropic hormones in the pituitary gland, but one can not exclude the possibility of its immediate effect on the peripheral endocrine glands and other organs. Apparently, under the influence of stimuli from the external environment, the epiphyses produce not one, but several compounds that fall mainly into the blood. These substances modulate the activity of monoaminergic neurons in the central nervous system that control the production of liberins and statins by certain structures of the brain and thereby influence the synthesis and secretion of tropic hormones in the pituitary gland. The influence of the epiphysis on the hypothalamic centers is predominantly inhibitory.

[1], [2], [3], [4]