Ind. J. Physiol. Pharmae., Volume 33, Number 4. 1989

REVIEW ARTICLE

THE PINEAL GLAND: ITS PHYSIOLOGICAL ANDPHARMACOLOGICAL ROLE

V. SRINIVASAN

Institute of Physiology,Madurai Medical College, Madura; - 625020

( Received on November 15, 1989 )

Abatract : Our perception of pineal gland function has attained new dimensions during the lastdecade. The gland is active throughout the life of an individual and aecretea melatonin, themajor 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 allo.

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 sexualmaturation. 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 areassociated with biological rhythm disturbances like sleep disorders, "jet lag" phenomena and

affective disorders. The gland is actively involved in the mechanisms controlling sleep­

wakefulneu 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 beconsidered an "equilibrating-tranquillizing gland" contributing to longevity.

Key word. : pineal gland

seasonal reproduction

chronobioticpsychotropic drugs

neuroendocrine-tranducer

sexual maturation

sleep-wakefulnessstress

pinealocyte

circadian rhythms

affective disorderlongevity

INTRODUCTION

Once considered to be an organ of little

functional significance, the pineal gland has nowemerged as a major "neuroendocrine transducer" (agland which converts a neural input into hormonaloutput) with specific effects on reproductive mecha­nisms, circadian organization. sleep mechanisms andcontrol of human mood. The gland acts as "ageneral synchronizing, stabilizing and moderatingorgan" for several physiological processes (I) andits hormone melatonin has been designated as"equilibrating hormone" (2).

The pineal gland of vertebrates develops fromthe neural crest ce])s of the roof of the diencephalon.In human beings it is deeply situated in the midlineof the brain below the corpus ca])osum. It is"ideally placed anatomically to co])ect. integrateand compare information from extra cranial sourcesand intracrnial sites" (3). Calcification which occursin the human pineal gland is considered to be aphysiological process related to its past secretory

activity rather than an indicator of present degenera­tion (4). Available evidence strongly indicates thatthe pineal gland is active throughout the life of anindividual (5).

264 Srinivasan

PINEAL GLAND STRUCTURE

The chief cellular component of the pineal glandis pinealocyte although other astrocyte like inter­

stitial 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). Thecytological nature of pinealocyte still remainsenigmatic although it contains the usual cellularorganelles like endoplasmic reticulum, golgi complex,lipid droplets, mitochondria and different types' ofsynaptic ribbons. Neuron specific enzyme enolasealso has recently been demonstrated in thesecells (6).

BIOSYNTHESIS OF PINEAL HORMONES

The pinealocytes of all vertebrates synthesize twodifferent types of substances, namely, indoles andpolypeptides. Melatonin, or 5-methoxy N-acetyl

Ind. J. Physio!. Pharmac., Volume 33, Number 4,1989

tryptamine, the major hormone of the pineal gland,was first isolated by Lerner in 1958 (9). Subse­quently many otber hydroxy and methoxy indoleshave been identified in the pineal gland. Thebiosynthesis of melatonin is given in Fig. I-A. Itbegins with conversion of the amino acid tryptophaninto S-hydroxytryptophan (5-HTP) by the enzymetryptophan hydroxylase. Decarboxylation of 5HTP

by 5-HTP decarboxylase gives rise to 5-hydroxy­tryptamine (5-HT) or serotonin. Serotinin IS

N-acetylated to form N-acetylserotonin by theenzyme serotonin N-acetyl transferase (SNAT) whichis the rate limiting enzyme in the bio-synthesis ofmelatonin. N-acetylserotonin is methylated to formmelatonin by the enzyme hydroxyindole O-methyltransferase (HIOMT). HIOMT is almost exclusivelyfound in the pineal gland, although recent studieshave demonstrated the presence of this enzyme inretina also. The synthesis of melatonin involvesmany other cofactors like S-adenosylmethionine,S-adenosylhomocysteine, and pteridines (10). Allother S-hydroxyindoles present in the pineal glandcan be methylated to form methoxy indoles like

Tryptophan

II Tryptophan hydroxylase

tS-hydroxytryptophan (S-HTP)

II S-HTP decarboxylase

i-5-hydroxytryptamine (S-HT) (Serotonin)

II Sertonin N acetyl transferase (SNAT)

tN-acetylserotonin

II Hydroxy indole a-methyl transferase (HIOMT)

tMelatonin

orN-acetyl S-methoxytryptamine

Fig. I-A: Biosynthesis of melatonin - the major pineal hormone

Ind.]. Physiol. Pharmac., Volume 33, Number 4,1989 The Pineal Gland 265

5-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 onlymelatonin and other two methoxy indoles likeS-methoxytryptophol and 5-methoxytryptamine.

Ultra structural and ultra cytochemical observa­vations have shown that pinealocytes are capable ofprotein secretion (7). With the use of bioassay,RIA (radioimmunoassay) and immunocytochemistrymany immunoreactive polypeptides have beenidentified in the pineal gland (l I). Arginine vaso­tocin (AVT), a tripeptide threonine-serine-Iysine,delta sle~p inducing peptide (DSIP), S-antigen, andCal bind in 27 are some of the recently identified

polypetides in the pineal gland of vertebrates (10,12),

Recently zinc-containing metallothionins also havebeen identified in the pineal gland of mammals (13).The principal route for the synthesis and secretionof proteins appears to be through endoplasmicreticulum, golgi complex and vesicular membranebound compartments (I I). The highly vascularpineal gland secretes their products directly into thecerebrospinal fluid, or into the perivascu lar spaces

HIOMT5-hydroxytryptophan ----+5-methoxytryptophan

IIt

HIOMT5-hydroxytryptamine ---.+5-methoxytryptamine

to be transported by the blood (7) According to

Wurtman (14) melatonin once formed is not storedwithin the pineal gland to any appreciable extent

but is released into the circulation directly.

REGULATION OF PINEAL GLANDSECRETION

The secretion of melatonin, the major pinealhormone is rhythmic in nature, with high levelsoccurring in the night and low levels during the day.This rhythm persists even when animals or humanbeings are housed in constant environmental condi­tions (e.g. continuous darkness) suggesting therebythat tbe rhythm is largely endogenous in nature (14).

The suprachiasmatic nucleus, the "master circadianclock", present in the hypothalamus, is largely

responsible for this endogenous melatonin rhythm(15). It controls the activity of the pineal glandthrough tbe release of norepinephrine from thesympathetic 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 thesuprachiasmatic nucleus by acting through tbe

II mono amino oxidase (MAO)

t. alcohol dehydrogenase a-acetyl transferase

5-hydroxymdoles acetaldehyde-- --+5-hydroxytryplophol --+O-acetyl 5-hydroxytryptophol

I I II aldehyde dehydrogenase I HIOMT \ HIOMT

t t tHIOMT

5-hydroxyindoleacetic acid----+5-methoxyindoleaceticacid 5-methoxytryptophol O-acetyl 5-methoxytryptophol

Fig. loB : Pathway showing the biosynthesis of hydroxy and methoxy indoles in the pineal gland

266 Srinivasan Ind. J. Phy.iol. Pharmac., Volume 33, Number 4, 1989

retinohypothalamic tract (17). The physiologicalsignificance of this mechanism is linked with thephotoperion con,trol of melatonin seeretion (14).

Electrophysiological and radioligand studies haveshown that light impulses reach the pineal glalidalso through central pinealopetal projections (18).Many peptides like vasopressin, oxytocin, neuro­physin, vasoactive intestinal polypeptide (VIP) havebeen identified in the central pinealopetal projections(I I). Neurotransmitter receptor sites like betaadrenergic, alpha adrenergic, dopaminergic, seroto­nergic, GABAergic, glutamatergic, benzodiazepi­nergic, substance P-ergic, have been identifiedrecently in the pineal glands of mammals includinghuman beings. Extensive reviews on this aspecthave been elegantly brought out by Ebadi andGovitrapong (J 9, 20). These pineal receptor sitesare involved not only in the synthesis of melatoninand other methoxy indoles but also participate inthe "biological expression of hitherto unknownfunctions of the pineal gland (21).

PINEAL GLAND FUNCTIONS

The pineal gland exerts mo~t of its effects onbodily systems through the secretion of its majorhormone melatonin. Biochemical and electrophy­siological techniques have revealed that this hormoneacts mainly on mid brain. hypothalamus and suprachiasmatic nucleus, although other areas likehippocampus and substantia nigra have also beenimplicated (21). Melatonin increases the concentra­tion of serotonin and catecholamines in these areasof the brain (22). Since melatonin increases theconcentration of biogenic amines, and biogenicamines themselves participate in many of the normaland disturbed functions of the central nervoussystem like mood and sleep disorders, it is likelythat melatonin exerts some of its actions on bodilysystems by influencing biogenic amine transmissionin the central nervous system (21).

Melatonin, when administered in physiologicaldoses, mimics the light dark cycle in the induction

of photoperiod dependent responses (23). Thehormone acts as a conveyor of photoperiodicinformation which is interpreted differently indifferent times of the year (24). Hence in recentyears studies on pineal gland function have focussedmainly in seasonal cycles rather than on dailycycles (25).

Pineal Gland and Reproduction

The physiologic effects of melatonin on repro­ductive function in animals depend on the species,but suppression of gonadal function has been welldocumented as the primary effect of melatonin andrelated compounds in most of the species that havebeen studied (26). Initial studies carried out byWurtman and his coworkera (27) showed thatmelatonin exert. a direct inhibitory action ongonads. Studies carried out on neuroendocrine­reproductive axis revealed that melatonin acts onthe hypothalamic neurons where it reduces theamplitude and/or frequency of GnRH pulses andthereby exerts an inhibitory action on gonadsthrough 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 beenshown to regulate the physiological status of thereproductive system on a seasonal basis. The lengthof the photoperiod determines the reproductivecompetence in these animsls (23). Gonadal activityis initiated during short days and inhibited duringlong days. The innate ability of these organisms tomeasure the passage of time has adaptive significance.It enables them to synchronize their breedingbehaviour with the most favourable environmentalconditions when the chances of ~urvival of theiryoung ones \\-ill be great (29, 30). The fact thatmelatonin rhythm changed as a function of season

Ind. J. Physiol. Pharmac., Volume 33, Number 4, 1989 The Pineal Gland 267

Was first shown by Arendt (31) who clearly demons­trated that longer nights were associated with moreprolonged periods of high melatonin levels. Theinsertion of melatonin implants has been found topromote the onset of reproductive function in sheepeven when they were exposed to inhibitory photo­periods (32, 33). The reproductive responses couldreflect the presence of the "short day" produced bythe constant elevation in circulating melatonininduced by melatonin implants (34). The inductionof short photoperiod by careful administration ofmelatonin has been found to be of great commercialvalue in increasing either sheep breeding (35, 36) orgrowth of fur (37). Many studies also have pointedout that breeding in humans has two annual peaksand this has been attributed to the two distinct typesof photoperiodic responles based on geneticheterogeneity (38).

Pineal Gland and sexual maturation

The occurrence of precocious puberty in a fouryear old boy with a pineal tumour was described asearly as 1898 by O'Heubner. Studies carried out inrecent years suggest that human pineal's secretoryactivity is associated with pubescence (14). Kitayand Altschule (39) on the basis of an extensivereview of literature suggested that pineal gland hasantigonadotropic effect on human sexual maturation.

In all mammals including human beings theonset of puberty has been attributed to the pulsatilesecretion of gonadotrophin releasing hormone(GnRH) by the arcuate nucleus of the hypothalamus(40). Melatonin appears to have a direct and

continuous regulatory action on gonadotrophinsecretory pattern from infancy to the onset ofpuberty (41). In an extensive study carried out onhuman beings belonging to different age groups(I to 80 years) they noted a steady decline in thenocturnal plasma melatonin levels from infancy toearly adulthood and a steady maintenance of thelevels thereafter. In summarizing the evidence for

the probable involvement of pineal gland in humanpuberty they have noted that melatonin deserves avery thorough examination for a possible action inthe mechanism controlling human sexual maturation(42).

Pineal gland and circadian rhythms

Every organism exhibits certain kinds ofbiological periodicity which enable it to measure thepassage of time. The most important one amongthese is the circadian rhythm which 1I0incides withthe 24-hour light and dark cycle. Under normalcircumstances the endogenous rhythms are synchro­nized with or entrained to external events byenvironmental cues or zeitgebers (time givers) suchas light-dark cycle (43). The daily rhythms such asrest-activity, temperature, REM sleep mechanism,electrolyte and cortisol excretion, have been wellstudied in man and other animals and are said to"free run" in the absence of any time cues whenstudied in specially constructed isolation bunkers(44,45,46).

Investigation on the control of these circadianrhythms has revealed the presence of an internalmaster biological clock in the supra chiasmaticnucleus (SeN) of the hypothalamus (43). Lesionsof the supra chiasmatic nucleus abolish all knowncircadian rhythms in rodents (47).

Evidence for the possible involvement of pinealgland in the synchronization of circadian rhythmshas come from the early observations of melatoninbiosynthesis which exhibits a characteristic day andnight rhythm. Melatonin is said to be one of thenaturally occurring substances that affect circadianrhythmicity (48). A functional synthronizing rolefor the pineal gland was suggested by Armstronget al (25) who administered melatonin in various

physiological (10 microgram/kg body weight) andpharmacokgical doses (I mg/kg body weight) andnoted disruption of various behavioural rhythms in

268 Srinivasan

experimental animals. Tn human beings, suddenrapid transfer across several time zones duringintercontinental flights results in internal desynchro­nization, a phenomenon known as "jet lag". Short(49) first suggested that melatonin administrationafter an intercontinental flight would alleviate thejet lag phenomenon Melatonin administration hasbeen found to be really ery effective in alleviatingjet lag (24, 50). Tn an interesting study they alsonoted that late afternoon administration of melatoninhas been shown to phase advance the fatigue­alertness rhythm (24). Melatonin is said to have adirect effect nn the central rhythm generatingsystems and act as a circadian zeitgeber for dark~ess;

hence the expressi n "darkness hormone". Thefunction of the mammalian pineal gland is to adjustthe phase and synchronize internal rhythms byperiodic nocturnal release of melatonin Whenadministered in pharmacological doses, melatoninacts as a. powerful chronobiotic maintainingsynchronicity and preventing desynchrony withincirca9ian systems (51). It has a potential value intreating external desynchronization that may occurin some categories of people such as astronauts,submariners ond polar explorers and may be usefultherapeutically in treating such diseases associatedwith biological rhythm disturbances (I 4, 24, 51).All these studies point out that pineal gland playsan important role in the physiology of circadianorganization of vertebrates, although compellingevidence 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 pinealgland and its hormone melatonin participate in thephysiological regulation of sleep and sleepiness (52).Intrahypothalamic administration of melatonin

induced sleep in cats (53). Studies carried out inother animals also supported the sedative like effectof melatonin Following melatonin administration,sleep induction occurred in human beings also {54).

Ind. ]. Physiol. Pharmac., Volume 33, Number 4,1989

Vollroth et al (55) applied low doses of melatoninintranasally and found induction of sleep in healthy

human volunteers. A number of other investigatorsalso have noted that melatonin acted like thehypnotic agents (52). The hormone is believed tobe released in pulses during light phases of humansleep and its probable physiological function is toinduce deep sleep and to prevent awakening (56).Daily late afternoon administration of melatoninhas been shown to phase advance the timing ofsleep (35). The high rate of melatonin secretionduring night hours and the induction of sleep byexogenous melatonin suggests that one of thephysiologic functions of melatonin is to do with thetiming of sleep (14). A clinical condition known asdelayed sleep phase syndrome (DSPS) due toineffective entrainment to zeitgeber (periodic events)such as light dark cycle, has been documented. Tnthese patients the timing cf sleep onset is abnormal.Since melatonin seems to be the natural chronobioticit could be used effectively for correcting the sleepabnormality of these patients (51).

Melatonin and Human mood disorders

Depression, manIa or hypomania are thecommonest type of human mood disorders that aredescribed in the literature. From psychiatric pointof view depression covers a wide range of affectivestates which includes normal and abnormal moodswings. The etiology of morbid depression howeverremains unknown. Many biological theories havebeen put forward to explain the underlying causes ofdepressive illness.

Since some of these affective disorders are cyclicin nature, desynchronization of biological rhythmshas been suggested as the cause for the precipitation

of manic depressive diseases (57). With the recogni­tion of pineal gland involvement in the control ofvarious bodily rhythms, much attention has beenpaid in recent years linking pineal gland withaffective disorders. Hypo-functioning of the pineal

Ind. J. PhYliol. Pharmac., Volume 33, Number 4, 1989 The Pineal Gland 269

gland as reflected by decreased levels of melatoninin body fluids was first noted in the year 1979 byWetterberg (58). Many other investigators workingin different parts of the world have also confirmedthe presence of "low melatonin syndrome" in agroup of depressives (59). These stl.:dies revealedcertain forms of depressions could be due tobiochemical defects in the synthesis, release andactions of melatonin ((0). Supportive evidmce forthe invoh'ement of melatonin in affective disGrderscame from the studies of psychoactive drug adminis­tration in experimental animals and in patients withaffective di~orders. The tricyclic antidepressants(imipramine) and monoamine oxidase inhibitorantidepressants increase the pineal melatonin contentsignificantly 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 diagramdepicting the probable mechanism of action ofantidepressants in elevating melatonin concentrationof the pineal gland is shown in Fig. 2. Both thesedrugs lctivate the beta receptors of the pineal grandby elevating the norepinephrine concentrations atthe rect:ptor sites. A specific disease known as

seasonal affect.ve disorder (SAD) with regularlyoccurring winter depressions v. as first noted byRosenthal and his coworkers (68). Bright light was

found to be very effective in treating such disordersand it seems to act by altering the profile ofmelatonin secretion in these patients (69).

PINEALO.cY·TE

TRYPTOPHAN

! Try H

5 HTP

J,CAAAD)

SEROTONIN

J, NAT

NAS

+ HIOMTtMELATONIN

NE

~ CLOR£>YLlNE

e~)

NORADRENERrC

NERVE

TERMINAL

-<- SUPERIOR CERVICAL GANGLION

MEDIAL FORE BRAINBUNDLE

IBRAIN STEM RETICULAR

FORMATI'ON

J..SPINAL·CORD

L

RETINOHYPOTHALAMIC TRACT

ASUPRACHIASMATIC NUCLEIOF HYPOTHALAMUS

I

LIGHT

III

G?

Fig. 2 : Effecu of anti-depreAanu on pineal gland function.

270 Srinivasan Ind. J. Physio!. Pharmac., Volume 33, Number 4,1989

Other miscellaneous Junctions of the pienal gland

Recently a great number of studies have beendevoted to the study of pineal gland influences oncancer. Pineal gland extracts exert an inhibitoryeffect on tumour growth in experimental animalsand this growth inhibitory effect seems to be relatedto melatonin only and not shared by other indoles(70). Melatonin exerts an inhibitory effect onlywhere it is present in physiological concentrations(71) and the timing of melatonin administrationseems to be crucial for arresting tumour growth (72).

The pineal hormone melatonin has been foundto be antistressogenic in nature and it participatesin the overall neuroendocrine mechanism involvinghypothalamo-hypophyseal-adrenal system (3,73,74).

The gland has been suggested to play an impor­tant role in determining longevity (75). Longevityis believed to be regulated by a biological clockmechanism and pineal gland plays an important rolein synchronizing the function of this biologicalclock (76) According to Romijn (I) pineal glandis the natural tranql!illizing organ, the morphologicalsubstrate of the "seventh chakra", the gateway toperfect harmony and rest.

CONCLUSIONS

The pineal gland has now emerged as an organof major neuroendocrine importance. It is activethroughout life. Its secretion is regulated not only

by sympathetic nerve fibers but also by centralpinealopetal projections. Many neurotransmitter­

receptor sites have been identified in the pinealgland.

Melatonin, the major pineal hormone isresponsible for most of the gland's effects on bodilysystems. The pineal gland plays an established rolein controlling reproduction. Though it is mainlyantigonadotropic, it also has progonadal actions insome species of animals. In recent years there isgrowing evidence to suggest that pineal plays animportant role in the mechanism controlling sexualmaturation and puberty. Pineal hormene, mela­tonin, h2ls a potential value in treating diseasesassociated with biological rhythm disturbances. Thegland participates in the physiological regulaticn ofsleep and sleepiness. Since melatonin acts as an"equilibrating hormone" it plays an important rolein controlling not only human mood disorders andstress but is also helpful in fighting against cancer.In :summary, it can be said that pineal gland is agland with multiple functions, including possiblyeven tranqiIity and longevity.

ACKNOWLEDGEMENTS

Acknowledgements are due to Dr. (Mrs.) LalithaAnantha SUbramaniam, Director of Medical Edu­cation, Government of Tamilnadu, Dr. (Mrs.) TaraNatarajan, Dean, Madurai Medical College andDr. M. Ramaraj Director, Institute of Physiologyfor their help.

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