Physiology of the pineal gland (epiphysis)

The pineal gland, or epiphysis, is an outgrowth of the roof of the third ventricle of the brain. It is covered with a connective tissue capsule, from which strands extend inward, dividing the organ into lobes. The lobes of the parenchyma contain pinealocytes and glial cells. Among the pinealocytes, larger, lighter cells and smaller, dark cells are distinguished. A feature of the vessels of the pineal gland is, apparently, the absence of close contacts between the endothelial cells, due to which the blood-brain barrier in this organ is insolvent. The main difference between the pineal gland of mammals and the corresponding organ of lower species is the absence of sensitive photoreceptor cells. Most of the nerves of the pineal gland are represented by fibers of the cells of the superior cervical sympathetic ganglia. The nerve endings form networks around the pinealocytes. The processes of the latter contact the blood vessels and contain secretory granules. The pineal gland is especially noticeable at a young age. By puberty, its size usually decreases, and later calcium and magnesium salts are deposited in it. Such calcification often allows the epiphysis to be clearly seen on skull X-rays. The mass of the pineal gland in an adult is approximately 120 mg.

The activity of the pineal gland depends on the periodicity of illumination. In the light, synthetic and secretory processes in it are inhibited, and in the dark, they are enhanced. Light impulses are perceived by the receptors of the retina 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 nervous influences disappear, and the activity of the pineal gland increases. Removal of the upper cervical sympathetic ganglia leads to the disappearance of the rhythm of activity of intracellular enzymes of the pineal gland, participating in the synthesis of its hormones. Nerve endings containing noradrenaline increase the activity of these enzymes through cellular beta receptors. This circumstance seems to contradict the data on the inhibitory effect of excitation of sympathetic nerves on the synthesis and secretion of melatonin. However, on the one hand, it has been shown that under lighting conditions the serotonin content in the gland decreases, and on the other hand, the role of cholinergic fibers in regulating the activity of oxyindole-O-methyltransferase (OIOMT) of the pineal gland has been discovered.

Cholinergic regulation of pineal gland activity is confirmed by the presence of acetylcholinesterase in this organ. The superior cervical ganglia also serve as a source of cholinergic fibers.

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

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

Serotonin synthesis is thought to occur in light pinealocytes and is controlled by noradrenergic neurons. Cholinergic parasympathetic fibers regulate the release of serotonin from light cells and thereby its availability to dark pinealocytes, where noradrenergic modulation of melatonin formation and secretion also occurs.

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

In addition to the ambiguities regarding the true nature of the pineal gland hormone(s), there is also disagreement regarding the route of entry into the body: into the blood or into the cerebrospinal fluid. However, most evidence suggests that, like other endocrine glands, the pineal gland secretes its hormones into the blood. Closely related to this issue is the question of the central or peripheral action of pineal hormones. Animal experiments (primarily hamsters) have shown that pineal regulation of reproductive function is mediated by the pineal gland's influence on the hypothalamic-pituitary system, rather than directly on the sex glands. Moreover, the introduction of melatonin into the third ventricle of the brain decreased the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and increased the content of prolactin in the blood, whereas the infusion of melatonin into the portal vessels of the pituitary gland was not accompanied by a change in the secretion of gonadotropins. One of the sites of melatonin action in the brain is the median eminence of the hypothalamus, where liberins and statins are produced, regulating the activity of the anterior pituitary gland. However, it remains unclear whether the production of these substances changes under the action of melatonin itself or whether it modulates the activity of monoaminergic neurons and thus participates in the regulation of the production of releasing factors. It should be emphasized that the central effects of pineal hormones do not prove their direct secretion into the cerebrospinal fluid, since they can also get there from the blood. In addition, there is evidence of the effect of melatonin on the testes (where this substance inhibits the formation of androgens) and other peripheral endocrine glands (for example, weakening the effect of TSH on the synthesis of thyroxine in the thyroid gland). Long-term administration of melatonin into the blood reduces the weight of the testes and the level of testosterone in the serum even in hypophysectomized animals. Experiments have also shown that a melanin-free extract of the pineal gland blocks the effect of gonadotropins on the weight of the ovaries in hypophysectomized rats.

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

Among the many diverse effects of these compounds, their influence on the secretion of pituitary gonadotropins attracts the greatest attention. Data on the disruption of puberty in pineal gland tumors were the first indication of its endocrine role. Such tumors can be accompanied by both acceleration and deceleration of puberty, which is associated with the different nature of neoplasms originating from the parenchymatous and non-parenchymatous cells of the pineal gland. The main evidence of the antigonadotropic effect of pineal gland hormones was obtained on animals (hamsters). In the dark (i.e., under conditions of activation of the pineal gland function), animals show a pronounced involution of the genitals and a decrease in the LH level in the blood. In epiphysectomized individuals or under conditions of transection of the pineal nerves, darkness does not have such an effect. It is believed that the antigonadotropic substance of the pineal gland prevents the release of luliberin or its effect on the pituitary gland. Similar, although less clear, data were obtained in rats, in which darkness somewhat delays puberty, and removal of the pineal gland leads to an increase in the levels of LH and FSH in the blood. The antigonadotropic effect of the pineal gland is especially pronounced in animals with impaired function of the hypothalamic-pituitary-gonadal system by the introduction of sex steroids in the early postnatal period.

Epiphyseectomy in such rats restores sexual development. The antigonadotropic effects of the pineal gland and its hormones are also enhanced under conditions of anosmia and starvation.

Not only melatonin but also its derivatives, 5-methoxytryptophol and 5-oxytryptophol, as well as serotonin, have an inhibitory effect on LH and FSH secretion. As already noted, poorly identified polypeptide products of the pineal gland also have the ability to influence gonadotropin secretion in vitro and in vivo. One of these products (with a molecular weight of 500-1000 daltons) turned out to be 60-70 times more active than melatonin in blocking hypertrophy of the remaining ovary in unilaterally ovariectomized mice. Another fraction of pineal gland peptides, on the contrary, had a progonadotropic effect.

Removal of the pineal gland 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. Similar shifts occur in animals kept in conditions of constant illumination, and the opposite - in rats kept in the dark. It is believed that the pineal gland secretes a substance that prevents the influence of the prolactin-inhibiting factor (PIF) 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. Epiphyseectomy causes opposite changes. The active substance of the pineal gland 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 conditions of constant absence of light, the growth of animals slows down and the content of growth hormone in the pituitary gland decreases significantly. Epiphyseectomy removes the effect of darkness and sometimes accelerates growth by itself. The introduction of pineal gland extracts reduces the growth-stimulating effect of pituitary gland preparations. At the same time, melatonin does not affect the growth rate of animals. Perhaps some other epiphyseal factor (factors) inhibits the synthesis and secretion of somatoliberin or stimulates the production of somatostatin.

Experiments have shown that the influence of the pineal gland on the somatotropic function of the pituitary gland is not mediated by a deficiency of androgens or thyroid hormones.

In pineectomized rats, corticosterone secretion transiently increases, although the stress response of the adrenal glands after pinealectomy is significantly weakened. Corticosterone secretion increases under conditions of constant illumination, which is known to inhibit the activity of the pineal gland. There is evidence that pinealectomy weakens the compensatory hypertrophy of the remaining adrenal gland after unilateral adrenalectomy and disrupts the circadian rhythm of glucocorticoid secretion. This indicates the importance of the pineal gland for the implementation of the adrenocorticotropic function of the anterior pituitary gland, which is confirmed by a change in ACTH production by the pituitary tissue removed from pineectomized animals. There is no consensus in the literature regarding the active principle of the pineal gland that influences the adrenocorticotropic activity of the pituitary gland.

Removal of the pineal gland increases the content of melanocyte-stimulating hormone (MSH) in the pituitary gland, while the introduction of melatonin into the IG cerebral ventricle decreases 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 the hypothalamic production of the melanotropin-inhibiting factor MIF.

The influence of the pineal gland and its hormones on other tropic functions of the pituitary gland is less studied. Changes in the activity of peripheral endocrine glands may occur due to the direct action of epiphyseal factors. Thus, removal of the pineal gland leads to some 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 pineal gland 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 the iodine-concentrating function of the thyroid gland.

The pineal gland transplantation to the adrenal glands, without affecting the state of the fascicular and reticular zones of the cortex, almost doubled the size of the glomerular zone, which indicates a direct effect of pineal gland products on the cells producing mineralocorticoids. Moreover, a substance (1-meth-oxy-1,2,3,4-tetrahydro-beta-carboline) was isolated from the pineal gland, stimulating the secretion of aldosterone and therefore called adrenoglomerulotropin. However, data were soon obtained denying the physiological role of this compound and even calling into question the very existence of a specific adrenoglomerulotropic factor of the pineal gland.

There are reports that removal of the pineal gland reduces the functional activity of the parathyroid glands. There are also opposite observations. The results of studies of the effect of the pineal gland on the endocrine function of the pancreas are mostly negative.

At present, there are still many unresolved issues, particularly concerning the nature of the compounds produced by this gland. The least doubtful is the influence of the pineal gland on the secretion of tropic hormones of the pituitary gland, but the possibility of its direct effect on the peripheral endocrine glands and other organs cannot be ruled out. Apparently, under the influence of environmental stimuli, the pineal gland produces not one, but several compounds that enter primarily into the blood. These substances modulate the activity of monoaminergic neurons in the central nervous system, which control the production of liberins and statins by certain structures of the brain and thereby affect the synthesis and secretion of tropic hormones of the pituitary gland. The effect of the pineal gland on the hypothalamic centers is primarily inhibitory.

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