AMER. ZOOL., 16:93-101 (1976).
New Horizons of Pineal Research
RUSSELJ. REITER, ANDREW J. LUKASZYK, MARY K. VAUGHAN
AND DAVID E. BLASK
Department of Anatomy, The University of Texas Health Science Center at San Antonio,
San Antonio, Texas 78284
SYNOPSIS For years it was assumed that indoles, especially melatonin, were responsible for
the ability of the pineal gland to inhibit pituitary gonadotrophins and thus depress sexual
physiology. Recent studies have shown, however, that melatonin treatment in two species of
hamsters and in the rat is equivalent to pinealectomy in terms of its effect on reproduction.
For example, both pinealectomy and the subcutaneous implantation of melatonin prevents
darkness from depressing reproductive functions in experimental animals. Furthermore,
both treatments also block the changes in pituitary hormones which result from exposure to
short daily photoperiods. Such findings suggest that the active pineal principles may be
something other than indoles and, indeed, a considerable amount of evidence indicates that
polypeptides may account for the pineal's ability to inhibit reproduction. A theory is
presented for the cellular release of pineal polypeptides. In this scheme the pineal polypeptide hormones are exocytotically released from cells in conjunction with carrier proteins.
The hormone is then exchanged for calcium resulting in the liberation of the hormone into
the pineal capillaries and in the eventual deposition of calcium within the pineal gland. This
theory provides a working hypothesis for the release of pineal hormonal products and
explains the presence of calcified deposits within the pineal gland.
Considering that the bulk of what we
know about the pineal gland has accrued
within the last decade, virtually every aspect
of pineal investigation probably still falls
into the category of a new horizon. This
potent gland apparently influences an uncommonly large number of functions. Indeed, all organs or organ systems in the
body fall under the influence, either directly or indirectly, of pineal hormonal
products. Besides its now well-known
interactions with the anterior pituitary
hormones (Reiter I974a,b), studies indicate
that the pineal may also be related to such
widely diverse functions as immune reactions (Jankovic et ai, 1970), alcohol ingestion (Reiter et al., 1973), activity and behavior (Quay, 1971; Sampson and Bigelow,
1971), myelination in the central nervous
system (Relkin et al., 1973), brain neurotransmitter metabolism (Wendel et al.,
1974), control of posterior pituitary secretion (de Vries and Kappers, 1971), growth
of malarial parasites (Arnold et al., 1969),
and tumor growth (El-Domeiri and Das
Gupta, 1973). It would obviously be impossible in this brief resume to discuss each of
these potentially important areas of investigation. Rather, the review will be concerned with what many investigators considered to be the so-called facts in our
knowledge of the pineal gland. Whereas it
was once regarded that the indoles (especially melatonin) were the pineal constituents which regulate the neuroendocrine
axis (Collu and Fraschini, 1972; Wurtman,
1973), interest has now shifted to polypeptides as the hormonal envoys of the
pineal gland (Benson and Orts, 1972;
Moszkowska et al., 1973). This has been
particularly apparent at the present symposium where several papers have been devoted solely to considerations of the biochemistry and physiology of the pineal
Work by the authors was supported by Grant GB43233X from the National Science Foundation, Grant polypeptides.
M74.87 from the Population Council, and a grant
The first international symposium confrom the San Antonio Area Foundation. R. J. R. is a
U.S.P.H.S. Career Development Awardee, HD- cerned with the pineal gland as an organ of
42398. M. K. V. is a U.S.P.H.S. Postdoctoral Fellow, internal secretion was held about a decade
AM-55966.
ago (Kappers and Schade, 1965). With the
93
94
REITER, LUKASZYK, VAUGHAN, AND BLASK
rapidly advancing state of the art since that
time, several other meetings have been organized to consider exclusively the various
aspects of pineal function (Reiter, 1970;
Wolstenholme and Knight, 1971) and two
books have been published which have
dealt primarily with the biochemistry of the
gland (Wurtman et al., 1968; Quay, 1974).
These works, along with the present symposium, emphasize the multifaceted nature
of the pineal gland as well as point out the
widespread interest that has been generated in reference to this diencephalic structure.
PINEAL INDOLES. ARE THEY ANTIGONADOTROPHIC FACTORS?
The biochemistry of indole synthesis
within the mammalian pineal gland has
been carefully studied (Weiss and Strada,
1972; Axelrod, 1974). The organ forms a
family of indoles, the best known of which is
7V-acetyl-5-methoxytryptamine (melatonin). Under experimental conditions, several of the indoles possess gonad-inhibiting
capabilities (Vaughan et al., 1972). However, the greatest research emphasis has
been directed toward identitying the endocrine role of melatonin (Wurtman, 1969,
1973; Collu and Fraschini, 1972).
When given to intact animals, melatonin
usually inhibits sexual physiology (Chu et
al., 1964; Moszkowska, 1965) and reverses
the stimulatory effects of pinealectomy on
the growth of the sexual organs (Wurtman
et al., 1968). These data were almost always
obtained from studies in which the rat was
the experimental animal, and characteristically, when injected peripherally, rather
large amounts of melatonin had to be.administered. The inhibitory reproductive effects of melatonin, with only a few exceptions, were usually modest and seemingly
were not sufficiently damaging to the sexual organs so as to jeopardize the reproductive potential of the animals. In still other
experiments melatonin either completely
lacked gonad-inhibiting activity (Ebels and
Prop, 1965; Talbot and Reiter, 1973/74) or
it was stimulatory (Thieblot et al., 1966) to
the gonads of rats.
When administered centrally, i.e., either
into the cerebrospinal fluid (CSF) (Kamberi, 1973) or directly into the brain (Fraschini and Martini, 1970), melatonin depressed both pituitary and plasma levels of
luteinizing hormone (LH). After testing
several pineal indoles, Fraschini and Martini (1970) concluded that two compounds,
melatonin and 5-hydroxytryptophol, specifically inhibit LH while two others,
5-methoxytryptophol and serotonin, are
the pineal hormones responsible for the
regulation of follicle stimulating hormone
(FSH). They also theorized that these
pineal principles act on specific indole- and
methoxyindole-sensitive receptors localized in the hypothalamus and midbrain.
The existence of such receptors as well as
their localization are far from proven. Additionally, the results of Kamberi (1973) do
not support the concept that melatonin has
a selective inhibitory influence on LH.
Generally, the role that melatonin plays in
the neuroendocrine system under experimental conditions remains to be clarified
and whether it has any role in normal hypothalamo-pituitary interactions also requires
definition.
One fact that seemingly argues against
melatonin being the pineal antigonadotrophin in rats is that its peripheral injection has only subtle effects on the endocrine
system. However, this may merely mean
that melatonin is rapidly metabolized when
it is in the blood and that it is normally
secreted into the CSF. On the other hand, is
there reason to suspect that any pineal substance, regardless of its route of secretion,
would be capable of inducing complete reproductive failure in the rat? Indeed, the
pineal itself in this species has rather slight
effects on sexual physiology. For example,
prepubertal pinealectomy only slightly accelerates pubertal onset, and light deprivation, which is believed to be a stimulus for
pineal antigonadotrophic activity, retards
but certainly does not prevent sexual maturation (Reiter, 1974a). For this reason, to
get a better idea of the role of melatonin, it
is reasonable to examine its effects in
species where the pineal exerts a marked
influence on the reproductive system.
One such species is the golden hamster
95
ENDOCRINE CONTROL OF MELATONIN SYNTHESIS
sexual organs (Reiter, 1974a). In fact,
length of the daily photoperiod (less than melatonin has been shown to have directly
12 hr of light per day) leads to pineal- opposite actions. When given to hamsters
induced collapse of the gonads and adnexa. as a subcutaneously implanted pellet (with
Light restriction in such experiments has beeswax), melatonin blocked the pineal
been achieved under laboratory conditions gland from inducing atrophy of the testes
by blinding the animals (Hoffman and Rei- and accessory organs and also obviated the
ter, 1965) or by placing them in short daily fall in pituitary prolactin levels normally
photoperiods (Reiter, 1973). If kept under associated with restricted photoperiods
natural photoperiods, when day length (Reiter et al., 1974) (Fig. 2). Other procefalls below 12 hr of light per day (during the dures which are capable of preventing
winter months) the gonads also involute darkness from inducing gonadal regres(Czyba et al., 1964). In all these cases, dark- sion in the hamster are removal of the
ness is incapable of forcing regression of pineal gland or its sympathetic denervathe neuroendocrine-reproductive axis if tion. Thus, melatonin treatment, rather
the animals have been pinealectomized than inhibiting sexual functions, dupli(Reiter, 1973, 1974ft) (Fig. 1).
cated the effects of pinealectomy. At about
From the results of such studies it is read- the same time, Hoffman (1974) found that
ily apparent that the pineal gland is quite in the Djungarian hamster (Phodopus suncapable of completely controlling the gorus) melatonin is also capable of acting in
breeding capability of the hamster. Despite a manner analogous to pinealectomy.
this, however, in this species melatonin has These findings certainly are not consistent
no demonstrable inhibitory influence on with melatonin being the pineal antieither the growth or the functioning of the gonadotrophic principle in these species.
(Mesocricetus auratus). Merely restricting the
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0.4-,
-
1
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0.3-
2.0-
1
-800
1
-600
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z
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O
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o
r\ _
-200
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r300
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PINX ?88 ...
FIG. 1. Testicular and accessory organ (seminal vesicles and coagulating glands) weights and pituitary prolactin levels in male hamsters kept under natural
photoperiodic conditions and autopsied in midJanuary. Unless pinealectomized (PINX), short winter
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i
I
INTACT
UJ
o
z
o
z
o
- 100
-200
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o
photoperiods depressed each of these parameters of
reproductive physiology. Pituitary prolactin values are
expressed in reference to a pool of standard hamster
anterior pituitaries (SHAP). Standard errors are designated by the vertical bars.
96
REITER, LUKASZYK, VAUGHAN, AND BLASK
300
-.
OQ.
03-
100
0.
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INTACT
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MEL
LOI 23
FIG. 2. Testicular and accessory organ (seminal vesicles and coagulatingglands) weights and pituitary prolactin levels of maJe hamsters kept in either long (LD
14:10) or short (LD 1:23) daily photoperiods. Both
pinealectomy (PINX) and melatonin treatment (MEL)
prevent the atrophic responses of the sexual organs
and the depression in pituitary prolactin levels which
accompany exposure to short daily photoperiods.
Pituitary prolactin values are expressed in reference to
a pool of standard hamster anterior pituitaries
(SHAP). Standard errors are indicated by the vertical
bars.
In subsequent dose-response studies, it was
found that as little as 50 ju,g of melatonin,
implanted subcutaneously every other
week, was sufficient to prevent reduced
photoperiods from curtailing the growth of
the genital organs (Reiter et al., unpublished).
At least two other pineal indoles, namely
5-methoxytryptophol (Reiter et al., 1975)
and 6-hydroxymelatonin (Reiter et al., unpublished) share melatonin's ability to
counteract the influence of short daily
photoperiods. The effects of weekly implantations of either of these compounds
into light-deprived hamsters resemble
those produced by pineal removal. By
comparison, N-acetylserotonin (the precursor of melatonin) and 5-hydroxytryptophol (the precursor of 5-methoxytryptophol) lack the ability to prevent the gonads
of light-restricted hamsters from involuting.
As noted earlier in this review, most of
the data illustrating melatonin's antigonadotrophic capabilities have been obtained in experiments where the rat was the
experimental model. In light of the results
summarized above, the first inclination is to
speculate that melatonin acts in one manner in the rat and in the opposite manner in
the hamster. However, since hamsters and
rats are closely related phylogenetically,
this explanation did not seem to suffice.
Unlike in hamsters, simple light restriction in the rat does not cause very severe
decremental changes in the gonads or
adnexa. However, combined blinding and
anosmia is associated with rather marked
hypotrophy of the sexual organs (Reiter,
1974a). Pinealectomy is capable of negating
the inhibitory effects of blinding and anosmia. The question arose, would melatonin
treatment duplicate the effects of pineal
removal in this rat model system? When
tested, weekly subcutaneous implants of
melatonin-beeswax pellets were equally as
effective as pineal removal itself in preventing the damaging effects of combined eyelessness and anosmia on the maturation of
the reproductive system (Reiter et al., unpublished). Thus, melatonin's action seems
to be identical in both the hamster and the
rat and under the conditions of these experiments the indole was certainly not antigonadotrophic.
There are several possible mechanisms
whereby melatonin could have negated the
influence of the pineal gland on the hypothalamo-pituitary-gonadal axis in rats and
hamsters (Reiter et al., 1974, 1975). First,
ENDOCRINE CONTROL OF MELATONIN SYNTHESIS
the indole may have been directly stimulatory to the genital organs. This notion gains
no support from other experimental work.
Another possibility is that melatonin stimulated the release of a progonadotrophic
substance either from the pineal gland or
from another organ in the body. The existence of a progonadotrophic pineal principle has been suggested but the evidence is
not compelling (Moszkowska et al., 1971).
Thirdly, melatonin may have acted on the
hypothalamus to raise its threshold so it
could no longer be inhibited by darkness
acting by way of the pineal gland. This explanation would require a pineal hormone
other than melatonin which normally is
capable of suppressing the neuroendocrine
axis. Many other pineal antigonadotrophic
factors, mostly polypeptides, have been isolated (Benson and Orts, 1972).
A final explanation requires that melatonin acts within the pineal gland itself to
prevent either the formation or the discharge of the real pineal antigonadotrophic
factor. This concept is diagrammatically
summarized in Figure 3. According to this
provisional scheme, exogenously administered or endogenously formed melatonin
may either restrict the production of the
polypeptidic gonad-inhibiting substance (2
in Fig. 3) or it may prevent the transfer of
the formed hormone from the secretory
cell into the blood vascular system (3 in Fig.
3). Either of these would effectively restrict
the antigonadotrophic activity of the pineal
gland. In the figure, polypeptides are designated as pineal hormones. This designation was selected since a great many gonadinhibiting polypeptides have been isolated
from pineal tissue (Moszkowskaet al., 1971;
Benson and Orts, 1972). However, the possibility that the reproductively active constituent of the pineal may be yet another
type of compound should not be overlooked. Quay (1974) has previously alluded
to a potential intrinsic action of melatonin
within the pineal gland, but the significance
of such an action was not specified.
In view of the aforementioned results, it
is difficult to imagine how melatonin, or
5-methoxytryptophol, could be the normal
antigonadotrophic agent of the pineal
gland. These compounds are, in fact, capa-
97
PINEALOCYTE
ymelatomrv
2 2
\
serotonin
polypeptides
\
tryptophon
PINEAL
CAPILLARY
FIG. 3. Theoretical relationships between the pineal
indoles, represented by melatonin, and pineal polypeptides. Melatonin may inhibit either the formation
(2) or the release (3) of the hypothetical polypeptide
hormones. Melatonin is known to gain access (1) to the
blood vascular system but whether pineal polypeptides
are secreted (4) remains to be determined.
ble of overcoming the gonad-inhibiting
ability of the gland. Yet, under certain circumstances the indoles can suppress reproductive activity (Wurtman et al., 1968;
Collu and Fraschini, 1972). These may be
pharmacologic actions of melatonin in that,
characteristically, substantial quantities of
the substance must be administered. It appears certain that the chemical nature of
the pineal antigonadotrophic principle remains to be established.
PINEAL POLYPEPTIDES: MECHANISMS OF SECRETION
There is an abundance of evidence which
indicates that the pineal forms and possibly
secretes polypeptide hormones. Judged
from what is known of another diencephalic derivative, the posterior pituitary,
the release of polypeptides by the pineal
gland could be expected. The mammalian
posterior pituitary is known to secrete at
least two hormones, vasopressin and oxytocin, both of which are small polypeptides
(Share and Grosvenor, 1974). The pineal
polypeptides that have so far been isolated
are seemingly structurally very similar to
vasopressin and oxytocin (Pavel and Pet-
98
REITER, LUKASZYK, VAUGHAN, AND BLASK
rescu, 1966; Moszkowska et al., 1971; Benson and Orts, 1972).
Accepting the fact that the pineal gland
does discharge polypeptides into some bodily fluid and with our knowledge of the
neurohypophyseal hormones as a guide, it
is possible the pineal polypeptides are
transported within and released from the
cells in conjunction with a carrier protein.
The carrier proteins for vasopressin and
oxytocin have been designated neurophysin II and neurophysin I, respectively
(Burford et al., 1971).
The reports of polypeptides in pineal extracts prompted Krass and colleagues
(1971) also to search for carrier proteins in
pineal tissue. They succeeded in isolating a
peptide-binding protein from the pineal
which almost completely lacked sulphurcontaining amino acids in contrast to the
usually high proportions found in the
neurophysins from the posterior pituitary
gland. The amino acid composition of
pineal and posterior pituitary peptide binding proteins were similar with respect to the
proportion of constituent acidic, neutral,
and basic residues. Krass et al., (1971)
elected to identify tentatively the pineal
carrier protein as "epiphysin" and concluded that its concentration was about
one-tenth that of neurophysins in the
neurohypophysis.
More recently, Reinharz et al. (1974) extracted and purified from bovine pineal tissue neurophysin-like proteins which
shared biochemical and immunological
properties with the neurophysins. They
claimed that the pineal neurophysin-like
protein and the posterior pituitary neurophysins have the same elution volume on
Sephadex G-75 and the pineal material was
recognized by anti-neurophysin antisera.
On polyacrylamide gel electrophoresis the
pineal fraction yielded two protein bands
that had the same Rf as neurophysin II and
neurophysin I, respectively. The findings
of both Krass et al. (1971) and Reinharz and
colleagues (1974) are consistent with the
idea that pineal neurophysin-like carrier
proteins exist and that they are released
from the cell in conjunction with small
polypeptides.
The prevailing theory for the secretion
of vasopressin (with its accompanying
neurophysin) involves its exocytotic release
from the cell with the subsequent exchange
of the vasopressin molecule for Ca2+ (Douglas^ al., 1971). It is conceivable that a similar mechanism is operative in the pineal
gland. Indeed, after extensive histochemical tests on bovine and ovine pineal
glands, Lukaszyk and Reiter (1974; unpublished) concluded that the liberation of
polypeptides within the pineal may involve
several processes common to the neurohypophysis. This scheme is depicted diagrammatically in Figure 4. The pineal secretory cells—which may be either the
pinealocytes, glial cells, or neurons—exocytotically extrude into the extracellular
space the polypeptides in conjunction with
hypothetical carrier proteins. During this
process the exocytotic microvesicles, in total
or in part, are also discharged into the
extracellular space where they reside as
exocytotic debris (Fig. 4). As in the posterior pituitary, it is hypothesized that blood
Ca2+ is then exchanged with the polypeptide hormone resulting in the release of the
hormone into the blood vascular system. As
a by-product of this process, a calciumcarrier protein complex is formed within
the extracellular space and eventually secondarily calcifies the exocytotic debris. This
results in the formation of calcified deposits
(corpora arenacea) which are commonly
encountered in pineal glands of many
species.
In addition to allowing for the discharge
of pineal polypeptides, the above mentioned theory also explains the formation
of the calcified deposits. These have long
been a mystery and were most commonly
considered to represent atrophic processes
within the gland. This notion is without
experimental basis, however. For example,
Wurtman et al. (1964) have shown that
there is no correlation between the degree
of calcification in the human pineal and the
activity of certain pineal enzymes. When
pineal tissue of individuals 1 to 80 years of
age was analyzed, the activity of hydroxyindole-O-methyltransferase, monoamine
oxidase, and histamine-N-methyltransferase remained essentially constant. Other
workers (Cassano et al., 1961; Wildi and
99
ENDOCRINE CONTROL OF MELATONIN SYNTHESIS
calcified
deposit
exocytotic
debris ,
secretory
cell
CALCIUM-CARRIER
HORMONE-CARRIER
COMPLEX
capillary
FIG. 4. Provisional scheme for the secretion of
pineal polypeptide hormones. The secretory cells may
be pinealocytes, glial cells, or neurons. The hormone
(polypeptide) is theoretically released in conjunction
with a carrier protein by an exocytotic process. The
Frauchiger, 1965) found no correlation between the number of calcified deposits and
the histological appearance of the pineal
parenchyma with no evidence of involution
of the organ with advancing age. According
to the theory presented here, the degree of
calcification may be directly related to the
past secretory activity of the organ. The
more calcified deposits, the more likely the
gland is to be hyperactive. The idea is supported in part by the findings of Khelimsky
(1969) as well. He histochemically identified a "colloid" substance in human pineal
tissue which he believed to be a by-product
of hormonopoiesis. This "colloid" may well
be the debris produced by the extrusion of
the microvesicles at the time of exocytotic
release of the hormone-carrier protein
complex. The implication of Khelimsky's
studies is that the "colloid" provides the
matrix for the deposition of calcium and
the formation of the corpora arenacea.
hormone is exchanged for calcium with the calcium
forming a complex with the carrier molecule. The
calcium-carrier complex then secondarily calcifies the
exocytotic debris resulting in the formation of corpora
arenacea.
CONCLUDING REMARKS
Generally, the roles that the indoles and
polypeptides play in determining the antigonadotrophic activity of the pineal gland
still require definition. On a weight basis,
the polypeptides seem to have much greater antigonadotrophic activity than the indoles. However, whereas it is known that
melatonin gets into the systemic circulation,
there is little evidence that the polypeptides
are released from the secretory elements of
the pineal gland. Many organs in the body
may contain polypeptides that inhibit reproductive physiology but, unless released,
they are functionally unimportant in this
regard. On the other hand, even if the
polypeptides are not discharged from the
gland, their potential usefulness as antifertility agents more than justifies the
search for these compounds. The theory of
release of pineal polypeptides that is pre-
100
REITER, LUKASZYK, VAUGHAN, AND BLASK
148:1609-1611.
sented is consistent with our knowledge of
the liberation of the neurohypophyseal Hoffman, K. 1974. Testicular involution in short
photoperiods inhibited by melatonin. Naturwissenhormones.
schaften 61:364-365.
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