Our perception of
pineal gland function has attained new dimensions during the last decade. The
gland is active throughout the life of an individual and secretes melatonin, the
major pineal hormone, and many indoles and polypeptides. The secretion of
pineal gland is regulated not only by sympathetic nerve fibers but by other
central pinealopetal projections also, Many neurotransmitter-receptor sites
have been identified recently in the pineal gland. The gland plays an
established role in controlling reproduction and is involved in the control of sexual
maturation. It has a major influence on the circadian organization of
vertebrates including human beings. The hormone melatonin has a potential
therapeutic valve in treating disorders that are associated with biological
rhythm disturbances like sleep disorders, "jet lag" phenomena and
affective disorders. The gland is actively involved in the mechanisms
controlling sleep wakefulness cycle and human mood disorders. It actively
participates in the neuroendocrine mechanism controlling stress and acts even as
an oncostatic gland. The pineal gland may be considered an
"equilibrating-tranquillizing gland" contributing to longevity.
Once considered to be
an organ of little functional significance, the pineal gland has now emerged as
a major "neuroendocrine transducer" (a gland which converts a neural
input into hormonal output) with specific effects on reproductive mechanisms,
circadian organization, sleep mechanisms and control of human mood. The gland
acts as "ageneral synchronizing, stabilizing and moderating organ"
for several physiological processes (I) and its hormone melatonin has been
designated as “equilibrating hormone" (2).
The pineal gland of
vertebrates develops from the neural crest cells of the roof of the
diencephalon. In human beings it is deeply situated in the midline of the brain
below the corpus callosum. It is "ideally placed anatomically to collect, integrate
and compare information from extra cranial sources and intracrnial sites"
(3). Calcification which occursin the human pineal gland is considered to be a
physiological process related to its past secretor activity rather than an
indicator of present degeneration (4). Available evidence strongly indicates that
the pineal gland is active throughout the life of an individual (5).
The chief cellular
component of the pineal gland is pinealocyte although other astrocyte lik e
interstitial cells also have been identified recently (6). Pinealocytes are
extremely modified photoreceptorcells that represent the last step in the phylogeneticevolution
(7). The presence of opsin-retinalS-antigen in the pinealocytes suggests their
closerelationship to retinal photo-receptor cells (8). The cytological nature
of pinealocyte stilI remains enigmatic although it contains the usual cellular
organelles like endoplasmic reticulum, golgi complex, lipid droplets,
mitochondria and different types' of synaptic ribbons. Neuron specific enzyme
enolase also has recently been demonstrated in these cells (6).
BIOSYNTHESIS OF PINEAL
HORMONES
The pinealocytes of
all vertebrates synthesize two different types of substances, namely, indoles and
polypeptides. Melatonin, or 5·methoxy N acetyltryptamine, the major hormone of
the pineal gland, was first isolated by Lerner in 1958 (9). Subsequently many other
hydroxy and merhoxy indoles have been identified in the pineal gland. The biosynthesis
of melatonin is given in Fig. I-A. It begins with conversion of the amino acid
tryptophaninto 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan
hydroxylase. Decarboxylation of 5HTPby 5-HTP decarboxylase gives rise to
5-hydroxytryptamine (5-HT) or serotonin. Serotinin is N-acetylated to form
Nsacetylserotonin by theenzyme serotonin N-acetyl transferase (SNAT) which is
the rate limiting enzyme in the bio-synthesis ofmelatonin. N-acetylserotonin is
methylated to form melatonin by the enzyme hydroxyindole O-methyltransferase
(HIOMT). HIOMT is almost exclusively found in the pineal gland, although recent
studies have demonstrated the presence of this enzyme in retina also. The synthesis
of melatonin involves many other cofactors like
S-adenosylmethionine,S-adenosylhomocysteine, and pteridines (10). Allother
5-hydroxyindoles present in the pineal gland can be methylated to form methoxy
indoles like5-methoxytryptophan, 5-methoxytryptamine, 5-methoxyindole 3-acetic
acid and 5-methoxytrytophol. Figure I-B gives the bio-synthetic pathway for the
formation of all these methoxy indoles.
The biologically
active methoxy indoles include only melatonin and other two methoxy indoles
like5-methoxytryptophol and 5-methoxytryptamine. Ultra structural and ultra
cytochemical observations have shown that pinealocytes are capable of protein
secretion (7). With the use of bioassay, RIA (radioimmunoassay) and
immunocytochemistrymany immunoreactive polypeptides have been identified in the
pineal gland (11). Arginine vasotocin (AVT), a tripeptide
threonine-serine-lysine, delta sleep inducing peptide (DSIP), S-antigen, and Calbindin
27 are some of the recently identified polypetides in the pineal gland of vertebrates
(10,12).
Recently
zinc-containing metallothionins also have been identified in the pineal gland
of mammals (13). The principal route for the synthesis and secretion of
proteins appears to be through endoplasmicreticulum, golgi complex and vesicular
membrane bound compartments (I I). The highly vascular pineal gland secretes
their products directly into the cerebrospinal fluid, or into the perivascular spaces
to be transported by the blood (7) According to Wurtman (14) melatonin once
formed is not stored within the pineal gland to any appreciable extent but is
released into the circulation directly.
The secretion of
melatonin, the major pinealhormone is rhythmic in nature, with high levels
occurring in the night and low levels during the day. This rhythm persists even
when animals or human beings are housed in constant environmental conditions
(e.g. continuous darkness) suggesting thereby that the rhythm is largely
endogenous in nature (14). The suprachiasmatic nucleus, the "master circadian
clock", present in the hypothalamus, is largely responsible for this
endogenous melatonin rhythm(15). It controls the activity of the pineal gland
through the release of norepinephrine from the sympathetic nerve fibres. (Fig.
2). Increased releaseof norepinephrine from the sympathetic nerve fibresin
night time increases the rate of synthesis ofmelatonin in the pineal gland
(16). Light-dark cycleentrains the melatonin rhythm generated by the suprachiasmatic
nucleus by acting through the retinohypothalamic tract (I7). The physiological
significance of this mechanism is linked with the photoperion control of
melatonin secretion (14).
Electrophysiological
and radioligand studies have shown that light impulses reach the pineal
glandalso through central pinealopetal projections (18). Many peptides like
vasopressin, oxytocin, neurophysin, vasoactive intestinal polypeptide (VIP)
havebeen identified in the central pinealopetal projections(II).
Neurotransmitter receptor sites like betaadrenergic, alpha adrenergic,
dopaminergic, serotonergic, GABAergic, glutamatergic, benzodiazepinergic,
substance P-ergic, have been identified recently in the pineal glands of
mammals including human beings. Extensive reviews on this aspect have been
elegantly brought out by Ebadi andGovitrapong (19,20). These pineal receptor sites
are involved not only in the synthesis of melatonin and other methoxy indoles
but also participate in the "biological expression of hitherto unknown
functions of the pineal gland (21).
The pineal gland
exerts most of its effects on bodily systems through the secretion of its major
hormone melatonin. Biochemical and electrophysiological techniques have
revealed that this hormone acts mainly on mid brain. hypothalamus and
suprachiasmatic nucleus, although other areas like hippocampus and substantia
nigra have also been implicated (21). Melatonin increases the concentration of
serotonin and catecholamine in these areas of the brain (22). Since melatonin
increases the concentration of biogenic amines, and biogenic amines themselves
participate in many of the normal and disturbed functions of the central nervous
system like mood and sleep disorders, it is likely that melatonin exerts some
of its actions on bodily systems by influencing biogenic amine transmission in
the central nervous system
Melatonin, when
administered in physiological doses, mimics the light dark cycle in the induction
of photoperiod dependent responses (23). The hormone acts as a conveyor of photoperiodic
information which is interpreted differently indifferent times of the year
(24). Hence in recent years studies on pineal gland function have focused mainly
in seasonal cycles rather than on daily cycles (25). The physiologic effects of
melatonin on reproductive function in animals depend on the species, but
suppression of gonadal function has been well documented as the primary effect
of melatonin and related compounds in most of the species that have been
studied (26). Initial studies carried out by Wurtman and his coworkers
(27) showed that melatonin exert а direct inhibitory action on
gonads. Studies carried out on neuroendocrine reproductive axis revealed
that melatonin acts on the hypothalamic neurons where it reduces the amplitude
and/or frequency of GnRH pulses and thereby exerts an inhibitory action on gonads
through the inhibition of gonadotrophin secretion(28).
In certain species of
animals like sheep and ewesmelatonin appears to be progonadal in nature. Thepineal
gland and its hormone melatonin have been shown to regulate the physiological
status of the reproductive system on a seasonal basis. The length of the
photoperiod determines the reproductive competence in these animsls (23).
Gonadal activityis initiated during short days and inhibited during long days.
The innate ability of these organisms to measure the passage of time has
adaptive significance.
It enables them to
synchronize their breeding behavior with the most favorable environmental
conditions when the chances of survival of their young ones will be great (29.
30). The fact that melatonin rhythm changed as a function of season Was first
shown by Arendt (31) who clearly demonstrated that longer nights were
associated with more prolonged periods of high melatonin levels. The insertion
of melatonin implants has been found to promote the onset of reproductive
function in sheep even when they were exposed to inhibitory photoperiods (32,
33). The reproductive responses could reflect the presence of the "short
day" produced by the constant elevation in circulating melatonin induced
by melatonin implants (34). The induction of short photoperiod by careful
administration of melatonin has been found to be of great commercial value in
increasing either sheep breeding (35, 36) or growth of fur (37). Many studies
also have pointed out that breeding in humans has two annual peaks and this has
been attributed to the two distinct types of photoperiodic responses based on genetic
heterogeneity (38).
The occurrence of
precocious puberty in a four-year old boy with a pineal tumor was described
asearly as 1898 by O'Heubner. Studies carried out in recent years suggest that
human pineal's secretor activity is associated with pubescence (14). Kitayand
Altschule (39) on the basis of an extensive review of literature suggested that
pineal gland has antigonadotropic effect on human sexual maturation.
In all mammals
including human beings the onset of puberty has been attributed to the
pulsatile secretion of gonadotrophin releasing
hormone(GnRH) by the arcuate nucleus of the hypothalamus(40). Melatonin appears
to have a direct and continuous regulatory action on gonadotrophin secretory
pattern from infancy to the onset of puberty (41). In an extensive study
carried out on human beings belonging to different age groups(1 to 80 years)
they noted a steady decline in the nocturnal plasma melatonin levels from
infancy to early adulthood and a steady maintenance of the levels thereafter.
In summarizing the evidence for thе probable involvement of
pineal gland in human puberty they have noted that melatonin deserves a very
thorough examination for a possible action in the mechanism controlling human
sexual maturation(42).
Pineal gland and
circadian rhythms
Every organism
exhibits certain kinds of biological periodicity which enable it to measure the
passage of time. The most important one among these is the circadian rhythm
which coincides with the 24-hour light and dark cycle. Under normal
circumstances the endogenous rhythms are synchronized with or entrained to
external events by environmental cues or zeitgebers (time givers) such as
light-dark cycle (43). The daily rhythms such as rest-activity, temperature,
REM sleep mechanism, electrolyte and cortisol excretion, have been
well studied in man and other animals and are said to "free
run" in the absence of any time cues when studied in specially
constructed isolation bunkers(44, 45, 46).
Investigation on the
control of these circadian rhythms has revealed the presence of an internal
master biological clock in the supra chiasmaticnucleus (SCN) of the
hypothalamus (43). Lesionsof the supra chiasmatic nucleus abolish all known
circadian rhythms in rodents (47). Evidence for the possible involvement of pineal
gland in the synchronization of circadian rhythms has come from the early
observations of melatonin biosynthesis which exhibits a characteristic day and
night rhythm. Melatonin is said to be one of the naturally occurring substances
that affect circadian rhythmicity (48). A functional synthronizing role
for the pineal gland was suggested by Armstrong et al (25) who administered
melatonin in various physiological (10 microgram/kg body weight) and
pharmacological doses (I rug/kg body weight) and noted disruption of various behavioral
rhythms in experimental animals. In human beings, sudden rapid transfer across
several time zones during intercontinental flights results in internal
desynchronization, a phenomenon known as "jet lag".
Short(49) first
suggested that melatonin administration after an intercontinental flight would
alleviate the jet lag phenomenon Melatonin administration has-been found to be
really very effective in alleviating jet lag (24, 50). In an interesting study
they also noted that late afternoon administration of melatonin has been shown
to phase advance the fatigue alertness rhythm (24). Melatonin is said to have a
direct effect on the central rhythm generating systems and act as a circadian
zeitgeber for darkness; hence the expression "darkness hormone". The
function of the mammalian pineal gland is to adjust the phase and synchronize
internal rhythms by periodic nocturnal release of melatonin When administered
in pharmacological doses, melatonin acts as a powerful chronobiotic maintaining
synchronicity and preventing desynchrony within circadian systems (5 I). It has
a potential value in treating external desynchronization that may occurring
some categories of people such as astronauts, submariners and polar explorers
and may be useful therapeutically in treating such diseases associated with
biological rhythm disturbances (I4, 24, 51).
All these studies
point out that pineal gland plays an important role in the physiology of circadian
organization of vertebrates, although compelling evidence for the full
involvement of this gland inthe control of circadian systems is yet to be
obtained.
Pineal gland and sleep
mechanism
There is enough
evidence to suggest that pineal gland and its hormone melatonin participate in
the physiological regulation of sleep and sleepiness (52). Intrahypothalamic
administration of melatonin induced sleep in cats (53). Studies carried out
in other animals also supported the sedative like effect of melatonin Following
melatonin administration, sleep induction occurred in human beings also
(54).
Vollroth et al (55)
applied low doses of melatonin intranasally and found induction of sleep in healthy
human volunteers. A number of other investigators also have noted that
melatonin acted like the hypnotic agents (52). The hormone is believed to be
released in pulses during IJght phases of human sleep and its probable
physiological function is to induce deep sleep and to prevent awakening (56). Daily
late afternoon administration of melatonin has been shown to phase advance the
timing of sleep (35). The high rate of melatonin secretion during night hours
and the induction of sleep by exogenous melatonin suggests that one of the
physiologic functions of melatonin is to do with the timing of sleep (14). A
clinical condition known as delayed sleep phase syndrome (DSPS) due to ineffective
entrainment to zeitgeber (periodic events)such as light dark cycle, has been
documented. In these patients the timing оf sleep onset is abnormal. Since
melatonin seems to be the natural chronobiotic it could be used effectively for
correcting the sleep abnormality of these patients (51).
Melatonin and Human
mood disorders
Depression, manиa or hypomania are the commonest type of human mood disorders that are
described in the literature. From psychiatric point of view depression covers a
wide range of affective states which includes normal and abnormal mood swings.
The etiology of morbid depression however remains unknown. Many biological
theories have been put forward to explain the underlying causes of depressive
illness. Since some of these affective disorders are cyclic in nature,
desynchronization of biological rhythms has been suggested as the cause for the
precipitation of manic depressive diseases (57). With the recognition of pineal
gland involvement in the control of various bodily rhythms, much attention has been
paid in recent years linking pineal gland with affective disorders.
Hypo-functioning of the pineal gland as reflected by decreased levels of melatonin
in body fluids was first noted in the year 1979 by Wetterberg
(58). Many other investigators working in different parts of the world have
also confirmed the presence of "low melatonin syndrome" in а group of depressives (59).
These studies revealed certain forms of depressions could be due to biochemical
defects in the synthesis, release and actions of melatonin ((0). Supportive
evidence for the involvement of melatonin in affective disorders came from the
studies of psychoactive drug administration in experimental animals and in
patients with affective disorders, The tricyclic antidepressants(imipramine) and
monoamine oxidase inhibitor antidepressants increase the pineal melatonin content
significantly in experimental animals (61,62,63,64).
These drugs elevate
the serum melatonin (6:). Urinary melatonin (59, 60 or urinary 6
hydroxymelatonin levels (67). A schematic diagram depicting the probable
mechanism of action of antidepressants in elevating melatonin concentration of
the pineal gland is shown in Fig. 2. Both these drugs ictivate the beta
receptors of the pineal grand by elevating the norepinephrine concentrations at
the receptor sites. A specific disease known as seasonal affect.ve disorder
(SAD) with regularly occurring winter depressions was first noted by Rosenthal
and his coworkers (68). Bright light was found to be very effective in treating
such disorders and it seems to act by altering the profile of melatonin
secretion in these patients (69).
Recently a great
number of studies have been devoted to the study of pineal gland influences on
cancer. Pineal gland extracts exert an inhibitory effect on tumor growth in
experimental animals and this growth inhibitory effect seems to be related to
melatonin only and not shared by other indoles(70). Melatonin exerts an
inhibitory effect only where it is present in physiological concentrations(71)
and the timing of melatonin administration seems to be crucial for arresting tumor
growth (72).
The pineal hormone
melatonin has been found to be antistressogenic in nature and it participates
in the overall neuroendocrine mechanism
involvinghypothalamo-hypophyseal-adrenal system The gland has been suggested to play an
important role in determining longevity (75). Longevity is believed to be
regulated by a biological clock mechanism and pineal gland plays an important role
in synchronizing the function of this biological clock (76) According to Romijn
(I) pineal gland is the natural tranquilizing organ, the morphological
substrate of the "seventh chakra", the gateway to perfect harmony and
rest.
CONCLUSIONS
The pineal gland has
now emerged as an organ of major neuroendocrine importance. It is active
throughout life. Its secretion is regulated not only by sympathetic nerve
fibers but also by central pinealopetal projections. Many neurotransmitter
receptor sites have been identified in the pineal gland.
Melatonin, the major
pineal hormone is responsible for most of the gland's effects on bodily systems.
The pineal gland plays an established role in controlling reproduction. Though
it is mainly antigonadotropic, it also has progonadal
actions in some species of animals. In recent years there is growing evidence
to suggest that pineal plays an important role in the mechanism controlling sexual
maturation and puberty. Pineal hormone, melatonin, has a potential value in
treating diseases associated with biological rhythm disturbances. The gland
participates in the physiological regulation of sleep and sleepiness. Since
melatonin acts as an "equilibrating hormone" it plays an
important rolein controlling not only human mood disorders and stress but is
also helpful in fighting against cancer.
In summary, it can be
said that pineal gland is a gland with multiple functions, including possibly even
tranquility and longevity.
