Human Reproduction Update 1996, Vol. 2, No. 3 pp.
225–235  European Society for Human Reproduction and Embryology
The pineal gland and reproduction
Vincenzo Aleandri, Vincenzo Spina1 and Alberto Morini
First Institute of Obstetrics and Gynaecology, Chair of Physiopathology of Human Reproduction, University of Rome
“La Sapienza”, Viale del Policlinico 155, 00161 Rome, Italy
TABLE OF CONTENTS
Introduction
Physiology of the pineal body
Role of the pineal in reproduction
Conclusion
References
The hormonal activity of the pineal gland is influenced
by both the dark–light cycle and the seasonal cycle,
causing it to play an important role in the neuro-
endocrine control of reproductive physiology. This is
especially evident in seasonally breeding animals, in
which reproductive function is clearly influenced by
seasonal variations in the duration of night and day.
Humans are not seasonal breeders. Nevertheless,
seasonal fluctuations have been described in human
reproduction, and the pineal gland also appears to
exert an important role in the neuroendocrine regula-
tion of human reproductive physiology. There is evi-
dence that the epiphysis is involved in the control of
sexual maturation. In rats, the maternal pineal
appears to influence the gonadal and genital develop-
ment and function of offspring; this hypothesis has yet
to be confirmed in humans. The pineal apparently in-
fluences human reproductive function not only at the
hypothalamic–pituitary level, by inhibition of the
hypothalamic pulsatile secretion of gonadotrophin-
releasing hormone, but also at the gonadal level, where
melatonin receptors have also been found. In addition,
melatonin is reported to increase serum prolactin con-
centrations in both rats and humans. It has been
suggested that melatonin is involved in the control of
menstrual cyclicity.
Key words: melatonin/pineal/reproduction
1To whom correspondence should be addressed. Phone: 39 6 855 2196; Fax: 39 6 704 52128
Introduction
The importance of the pineal gland was perceived long
225 ago: in the 16th century the gland was thought to be the seat
226 of the soul! However, it is only in the past three decades that
227 remarkable advances in the knowledge of the functional
232 significance of the epiphysis have been made. Through its
232 endocrine activity, via mechanisms and physiological
correlations that are not yet entirely understood, the pineal
regulates or takes part in the control of numerous functions
of an organism. Investigations in both animals and humans
have provided evidence that the gland plays an important
role in the regulation of both the circadian and seasonal
rhythms in a variety of species (Morgan and Williams,
1989; Namboodiri et al., 1991; Bartness et al., 1993;
Reiter, 1993; Weaver et al., 1993; Masson Pevet and Gauer,
1994) and in the endocrine control of reproductive physiol-
ogy (Kinson and Peat, 1971; Hoffman, 1973; Brzezinski
and Wurtman, 1988; Matthews et al., 1993). Furthermore,
epiphysis activity seems to be important in modulating the
activity of the immune system (Maestroni, 1993). In addi-
tion, several studies have investigated a possible role of the
gland in other physiological processes, such as the regula-
tion of body temperature (Saarela and Reiter, 1994) and
weight (Lerchl and Schlatt, 1993), the inhibition of tumoral
growth (Bartsch et al., 1991; Maestroni, 1993) and even an
influence on life span (Oaknin Bendahan et al., 1995).
Nevertheless, many of the observed physiological
correlations are still incompletely understood, and there
remains much to investigate about the activities and the
physiological role of this endocrine organ, especially in
humans. For this reason, the epiphysis is attracting the
interest of researchers. As regards reproduction, the gland
has been demonstrated to exert an important regulation on
seasonal reproductive changes in seasonally breeding ani-
mals. In humans, who are not seasonal breeders, the pineal
appears to be involved in the neuroendocrine regulation of
puberty and reproductive physiology; however, many
aspects of the role of the pineal in human reproduction
226 V.Aleandri, V.Spina and A.Morini
Figure 1. Retino-pineal pathway: noradrenergic fibres originating
from superior cervical ganglia have their terminals in the pineal.
remain obscure. The aim of this study is to update current
knowledge about the role of the pineal in reproductive
physiology.
Physiology of the pineal body
The pineal body is the only endocrine gland directly in-
fluenced by the external environment via the retina; in fact,
the gland converts environmental signals into neuroendo-
crine messages (Reiter, 1983; Binkley, 1993; Pevet, 1993).
The information is transmitted from the retinal photorecep-
tors to the suprachiasmatic nuclei, then to the paraventricular
nuclei and, through the intermediolateral cell column, to
the superior cervical ganglia. Noradrenergic fibres origin-
ating from superior cervical ganglia have their terminals in
the pineal body (Reiter, 1983; Klein, 1985; Binkley, 1993)
(Figure 1).
These fibres stimulate either β- or α-adrenergic recep-
tors of the pinealocyte (Arendt et al., 1985; Klein, 1985;
Vanecek et al., 1985). The activation of these receptors
synergically increases intracellular cAMP and cGMP: in
fact, α1-adrenoceptor activation has proved to significantly
potentiate β-adrenergic stimulation of both cAMP and
cGMP. The increase in intracellular cAMP enhances N-
acetyltransferase (NAT) activity (Klein, 1985; Sugden et
al., 1985; Vanecek et al., 1985). Thus serotonin, which is
produced in two steps (hydroxylation and decarboxyl-
ation) from tryptophan within the pinealocyte (Axelrod,
1974), is converted to N-acetylserotonin by NAT (Klein,
1979). N-Acetylserotonin is finally converted into the hor-
mone melatonin (5-methoxy-N-acetyltryptamine) by the
pineal-specific enzyme hydroxyindole-O-methyltrans-
ferase. Thus, NAT activity is under the control of the
retino-pineal pathway and represents the rate-limiting
factor of hormonal synthesis (Klein, 1979; Namboodiri et
Figure 2. Pathway for secretion of melatonin within the pinealocyte:
the N-acetyltransferase (NAT) activity, which is under the control of
the retino-pineal pathway (through the release of noradrenaline),
represents the rate-limiting factor in the synthesis of melatonin.
al., 1991) (Figure 2). Interestingly, a large nocturnal in-
crease in NAT activity has been demonstrated (Sugden et
al., 1985). Such an increase is mediated by noradrenaline
released from sympathetic nerve terminals in the pineal,
and it causes a notable increase in melatonin synthesis
during the night.
Melatonin is the major, or at least the most studied,
secretion product with which pineal physiological prop-
erties appear to correlate, but recent studies have also
ascribed importance for pineal function to other indoles
(Pevet, 1983). Melatonin is secreted into the blood with an
endogenous and individual rhythm synchronized by the
dark–light cycle: the plasma concentrations of the hormone
reach a peak during the night-time, at least in the absence of
light, and the persistence of high concentrations of melato-
nin is proportional to the duration of darkness (Goldman,
1991; Reiter, 1991, 1993; Pevet, 1993). Exposure to light
rapidly inhibits melatonin synthesis by the epiphysis and
its secretion into the blood. Thus, because of changes in the
duration of night and day, the rhythm of melatonin release
is also influenced by the cycle of the seasons. Indeed, the
pineal gland, through its hormonal secretion, informs the
whole organism about the current phase both of the day and
of the year (Reiter, 1991).
Melatonin secretion may, however, be influenced by
additional factors. Animal studies suggest that temperature
(Zatz et al., 1994) and social cues may affect melatonin

secretion and seasonal rhythms (Wayne et al., 1989).
Moreover, since the precursor tryptophan is supplied to the
gland by the circulating blood, dietary intake of tryptophan
may influence melatonin concentrations (Heuther et al.,
1992; Kennedy, 1994). Dopaminergic, serotoninergic,
γ-aminobutyrate and benzodiazepine receptors have also
been detected in the pineal (Ebadi and Govitrapong, 1986),
suggesting a possible role for these neurotransmitters in the
control of melatonin secretion. Experimental evidence
suggests that melatonin synthesis is in part under sero to-
ninergic control (Den Boer and Westenberg, 1990) and
may be suppressed by benzodiazepines (McIntyre et al.,
1993). In addition, it has been suggested that in the rat
melatonin controls its own rhythmic production by directly
entraining a circadian pacemaker modulating the NAT
activity rhythm (Humlova and Illnerova, 1990).
Role of the pineal in reproduction
The pineal in seasonal and non-seasonal breeders
The reproductive function shows both qualitative and
quantitative differences, related to the seasonal cycle
(especially winter and summer), in both females and males.
This feature is especially evident in animals that are sea-
sonal breeders, in which variations in the reproductive
cycle reveal they are timed by changes in the photoperiod
(Tamarkin et al., 1985). The pineal, through its endocrine
activity synchronized by the dark–light cycle, regulates
seasonal changes in the reproductive function of these
animal species (Reiter, 1991, 1993; Weaver et al., 1993). In
fact, changes in the duration of night and day that are asso-
ciated with the cycle of the seasons result in a different
secretory profile of melatonin: the nocturnal release of the
hormone is longer in duration in winter than in summer.
Long-day breeders, such as the hamster, are reproduc-
tively active during the summer, when the nights are
shorter; in these species the reproductive function de-
creases to a minimum in winter months, when the nights
are longer (Silman, 1993). By exposing hamsters to short
photoperiods, inhibition of the reproductive system is
obtained until there is testicular involution in males and
anoestrus in females (Hoffman, 1973; Lerchl and Nieschlag,
1992). The gonadal regression is followed by a return to
normal function, suggesting the development of insensitivity
of the reproductive axis to regressive photoperiods (Lerchl
and Nieschlag, 1992; Lerchl and Schlatt, 1993). In addi-
tion, gonadal development in pubertal hamsters is arrested
by exposure to short photoperiods (Buchanan and Yellon,
1991). Pinealectomy, however, prevents gonadal re-
The pineal gland and reproduction 227
gression in hamsters exposed to a short photoperiod
(Hoffman, 1979). With melatonin it is possible to mimic all
of these effects of photoperiod on the reproductive function
(Duncan et al., 1990; Buchanan and Yellon, 1991; Goldman,
1991; Badura and Goldman, 1992; Pevet, 1993). Thus, in
the hamster, melatonin plays an inhibitory role in reproduc-
tion. There is evidence to suggest that this antigonadal
action is exerted by inhibition of gonadotrophin-releasing
hormone (GnRH) (Buchanan and Yellon, 1991) (Table I).
In contrast, in short-day breeders such as the sheep
reproductive activity is associated with a decrease in the
length of the day, the breeding season being autumn and
winter. Melatonin exerts a stimulatory effect on the repro-
ductive axis in this species (Karsch et al., 1984). Studies in
pinealectomized ewes treated with long-term melatonin
infusion have reported that short-day melatonin patterns
produce an increase in the pulse frequency of luteinizing
hormone (LH) secretion (Bittman et al., 1985). Recently,
contemporaneous stimulation of GnRH and LH pulsatile
secretion by short-day-like melatonin administration has
been demonstrated (Table I), whereas LH release and
reproductive activity are inhibited by a long-day pattern of
melatonin (Viguie et al., 1995). It appears that melatonin
mediates the influence of photoperiod on LH pulsatile
secretion by driving the responsiveness to oestradiol nega-
tive feedback (Bittman et al., 1985). After pinealectomy,
ewes are unable to synchronize their reproductive
responses to seasonal changes in the duration of night and
day (Wayne et al., 1990; Woodfill et al., 1991, 1994).
The rat is a non-seasonal breeder, but in this species too,
reproductive function is influenced by photoperiod, mela-
tonin administration or pinealectomy. Light exposure and
pinealectomy are associated with an enhancement in
gonadal function (Kinson and Peat, 1971), while melatonin
administration is capable of delaying the onset of puberty,
blocking the pubertal increase in gonadotrophins and in-
hibiting naloxone-induced LH pulsatility (Aubert et al.,
1988). The onset of puberty is also sensitive to variations in
photoperiod (Ramaley and Bunn, 1972). Furthermore,
both the oestrous cycle and ovulation are reported to be
influenced by the pineal. Melatonin administration during
the pro-oestrous prevents the LH surge and ovulation (Ying
and Greep, 1973). There is also evidence that the pineal has
a role in the timing of the pro-oestrous LH surge in the rat
(Chiba et al., 1994). In-vitro studies suggest that melatonin
is capable of influencing hypothalamic GnRH secretion
(Rasmussen, 1993) and luteinizing hormone-releasing
hormone (LHRH)-induced pituitary LH release in this
species (Vanecek and Klein, 1992; Hattori et al., 1995)
(Table I).
228 V.Aleandri, V.Spina and A.Morini

Table I. Melatonin and reproduction of seasonal breeders, non-seasonal breeders and humans

Species Breeding season Influence of melatonin Effects of long-term melatonin Mechanism of action of melatonin
on HPO axis administration
Hamster spring–summer inhibitory delayed puberty GnRH inhibition
(long day breeder) Gonadal involution
Sheep autumn–winter stimulatory enhanced reproductive activity GnRH stimulation
(short day breeder) increased pulsatile LHRH and LH
Rat — inhibitory delayed puberty GnRH inhibition
(non-seasonal breeder) absence of the pro-oestrous LH surge GnRH-induced LH release
Anovulation inhibition
Human — inhibitory decreased plasma LH (with absence GnRH inhibitiona
of the mid-cycle surge), oestradiol & GnRH-induced LH inhibitiona
progesterone Direct action on gonads
Anovulation

GnRH = gonadotrophin-releasing hormone; LHRH = luteinizing hormone-releasing hormone; LH = luteinizing hormone; HPO =
hypothalamic–pituitary–ovarian.
aGnRH inhibition is more likely than GnRH-induced LH inhibition.

Central binding sites for melatonin-mediated
control of reproduction
Experiments utilizing microimplants of melatonin and
techniques involving destruction of specific brain areas
show that the target sites, which subserve the melatonin
control of seasonal responses, are the suprachiasmatic
nucleus in the Siberian hamster, the anterior hypothalamus
in the Syrian hamster, and the medio-basal hypothalamus
in the sheep (Bartness et al., 1993; Malpaux et al., 1993).
Autoradiographic techniques have localized the receptors
that mediate this role of melatonin to the pars tuberalis in
the rat and the Rhesus monkey, which are not seasonal
breeders (Nakazawa et al., 1991; Weaver et al., 1993), and
in many mammals (Gauer et al., 1994). Such receptors are
characterized by high affinity and highly species-specific
distribution (Reiter, 1993; Weaver et al., 1993). Further-
more, receptor density in the pars tuberalis of different
species of animals exhibits seasonal variations (Masson
Pevet and Gauer, 1994). Autoradiographic techniques
(using 125I-labelled melatonin) have also detected the pres-
ence of these receptors in the pars distalis in humans, but
with an inconsistent distribution, and their relative absence
in the pars tuberalis; such data suggest that there are differ-
ent neuroendocrine mechanisms of response to melatonin
in humans. Conversely, autoradiography has also localized
the receptors which mediate melatonin influence on circa-
dian rhythms to the suprachiasmatic nuclei (Weaver et al.,
1993). Data regarding central melatonin binding sites are
summarized in Table II.
environmental conditions and food supply. Humans are not
seasonal breeders: sexual activity is not related to season and
not necessarily connected with reproduction. Importance is
ascribed to food supply, artificial light, heating and social life
in reducing seasonal and circadian influence on human repro-
duction. Furthermore, especially in western countries, various
confounding factors must be taken into account: contracep-
tion, family planning, diet, stress (Rojansky et al., 1992). In
seasonally breeding species there is a relative uniformity of
the melatonin release pattern among individuals. In the adult
human, plasma concentrations of the hormone are on average
higher during the night than in the day; yet considerable inter-
individual differences have been reported not only in noctur-
nal serum melatonin concentrations, but in some cases also in
the secretion rhythm (Lerchl and Partsch, 1994). This may
represent the expression of evolutionary changes, or be due to
exposure to artificial light (Silman, 1993) or to the influence
of the other above-mentioned factors.
Table II. Central binding sites for melatonin-mediated control
of reproduction
Species Central target sites
Siberian hamster suprachiasmatic nucleusa
Syrian hamster anterior hypothalamusa
Sheep medio-basal hypothalamusb
Rat pars tuberalisc
Rhesus monkey pars tuberalisc
suprachiasmatic nucleusc
Human pars distalisc
suprachiasmatic nucleusc

The pineal in humans aAssessed by brain lesion techniques.

bAssessed by intracranial application of microimplants of
The seasonality of reproduction represents the mechanism by melatonin.
which nature ensures the occurrence of births at a time of the cAssessed by autoradiographic techniques (125I-labelled
year suitable for offspring survival, in relation to appropriate melatonin).

Seasonal trends in human reproduction
Although humans are not seasonal breeders, seasonal trends
in their reproductive function have been described. In a re-
cent study, seasonal variations in human conception and
birth rates in different geographical areas were analysed (Ro-
jansky et al., 1992). In particular, in northern countries, the
conception rate has been reported to be higher in summer
than in winter and, as a consequence, the birth rate reaches a
maximum in the spring season (Timonen et al., 1965; Puo-
lakka et al., 1985). In contrast, in hot climate areas of the
world, a peak in the conception rate during winter (Mathers
and Harris, 1983) and a decrease in the birth rate during
spring (Levine et al., 1990) have been documented. More-
over, the season in which there are peaks in the birth rate has
been found to be related to latitude (Batschelet et al., 1973).
In hot climates, where there is a minimal seasonal vari-
ation in photoperiod, temperature has been especially im-
plicated in producing seasonal changes in conception rates.
In northern countries, where the seasonal contrast in lumin-
osity is considerable, the photoperiod is more likely to
affect human reproductive axis activity (Rojansky et al.,
1992). During the dark season, reduced activity of the
anterior pituitary–ovarian axis (Kauppila et al., 1987b) and
an increase in serum melatonin have been documented by
population studies in such countries (Kauppila et al.,
1987a). In addition, the season is reported to affect plasma
concentrations of melatonin and LH significantly. Nocturnal
plasma melatonin concentrations on day 10 of the men-
strual cycle have been found to be higher in winter than in
summer. Conversely, nocturnal plasma LH levels are
higher in summer than in winter (Kivela et al., 1988). All of
these data are consistent with the above findings regarding
conception and birth rates in northern countries. With the
exclusion of a correlation with temperature in these
countries, it has been suggested that seasonal changes in
daylight, through melatonin secretion, may affect human
reproductive function (Kauppila et al., 1987a).
The conception rate may also be critically influenced by
nutritional status, diet, stress and weight loss. Various fac-
tors have been implicated in seasonal fluctuations in the
conception rate: frequency of intercourse, ovulation rate,
quality of ovum and zygote, endometrial receptivity and
sperm quality (Rojanski et al., 1992).
The importance of some of these factors is also sug-
gested by in-vitro fertilization results, which have also
been found to exhibit seasonality. In particular, seasonal
changes have been documented not only in the fertilization
and pregnancy rates, but also in the quality of the embryo
and the number of oocytes retrieved. Furthermore, such
seasonal differences have still been observed after adjust-
The pineal gland and reproduction 229
ing for number of oocytes retrieved. This may be related to
the quality of the oocyte or the spermatozoon, or to endo-
metrial receptivity (Stolwijk et al., 1994).
Seasonal effects on oocyte quality (Jongbloet, 1975) and
endometrial receptivity (Timonen et al., 1964) have been
described. As regards sperm quality, an investigation
carried out in Texas on 131 men reported that sperm con-
centration, count and motility were significantly lower in
summer. Furthermore, in the offspring of these men, a
significantly low birth rate was found to occur in spring
(Levine et al., 1990). Since temperature critically affects
spermatogenesis, changes in scrotal temperature have been
proposed as the major factor related to seasonal sperm
quality: the higher the temperature the lower the sperm
quality (Levine et al., 1990; Levine, 1991). It must be
remembered that melatonin reportedly plays an important
role in the thermoregulatory processes of an organism
(Saarela and Reiter, 1994), although no correlation with the
above data has been found so far. As regards the contribu-
tion of ovulation rate to seasonal conception rate, light
appears to have an influence. The sensitivity of ovulation to
light is suggested by the documented decrease in anterior
pituitary–ovarian function and increase in serum melato-
nin during the dark season in northern countries (Kauppila
et al., 1987b), where conception and multiple pregnancy
rates are higher in summer than in winter (Puolakka et al.,
1985).
Thus, available data seem to indicate that melatonin
partially mediates seasonal fluctuations in the human
reproductive function. This is also suggested by evidence
from some pathologies influenced by the season, such as
depression and seasonal affective disorders, which are
often associated with menstrual and ovulation irregular-
ities. Winter depression is reported to be linked to abnor-
mally delayed circadian rhythms; the onset of melatonin
secretion has been observed to occur later in these patients.
Phototherapy has proven to be effective for the treatment of
winter depression, by inducing the earlier onset of melato-
nin production with a phase advance of circadian rhythms
(Sack et al., 1990). Sensitivity to phototherapy has also
been described in seasonal affective disorders, which must
be regarded as a clinical category characterized by the triad
hypersomnia, hyperoxia and weight gain and, usually,
association with symptoms of depression. Interestingly,
these disorders appear to be influenced by latitude (Attar
Levy et al., 1990). Circadian abnormalities may also be
involved in the pathogenesis of pre-menstrual depression.
Phototherapy benefits patients suffering from this syn-
drome, in which an altered secretory profile of melatonin
has been observed (Parry et al., 1990).
230 V.Aleandri, V.Spina and A.Morini
The pineal and puberty
Experimental evidence indicates that the pineal plays an
important role in the neuroendocrine control of puberty in
animals (Ramaley and Bunn, 1972; Aubert et al., 1988;
Buchanan and Yellon, 1991). Melatonin also appears to be
involved in the endocrine modulation of human sexual
maturation. In humans, serum melatonin concentrations
are reported to decrease progressively with advancing age,
and reach values <450 pmol/l (∼100 pg/ml) at 10 years of
age (Attanasio et al., 1985; Waldhauser et al., 1988; Caval-
lo, 1992). The hypothalamic–pituitary–gonadal axis,
which is very active during fetal life and the first year of
life, remains quiescent until approximately the age of 10
years. After this, there is a reactivation of the hypotha-
lamic–pituitary axis. A progressive increase occurs in the
amplitude and frequency of GnRH pulses; consequently,
the pulsatile secretion of LH and follicle stimulating hor-
mone (FSH) increases similarly, with the subsequent onset
of pubertal phenomena (Sizonenko, 1989).
It has been reported in animals that, through its nocturnal
secretion of melatonin, the pineal exerts an inhibitory role
on the hypothalamus and on pubertal maturation (Sizonenko
et al., 1985; Buchanan and Yellon, 1991). Thus, it is likely
that melatonin also exerts a similar inhibitory effect on
GnRH hypothalamic secretion in humans. It has been
postulated that, before puberty, even if they progressively
decrease, melatonin concentrations are too elevated to
allow hypothalamic activation; however, at ∼9 or 10 years
of age the decline of serum melatonin below a threshold
value (∼500 pmol/l
115 pg/ml) represents the activating
signal for the hypothalamic pulsatile secretion of GnRH
and thereafter the onset of pubertal changes (Silman,
1991).
Since the production rate of melatonin does not change
with age, it has been suggested that the decreasing con-
centrations of melatonin seen with advancing age are due
to the increase in body mass (Waldhauser et al., 1988;
Young et al., 1988). However, according to another
hypothesis, the decrease with age of nocturnal serum mela-
tonin is not fully explained by an increase in body mass,
since even independently of weight the onset of sexual
maturation is significantly related to melatonin concentra-
tions (Waldhauser et al., 1991). Neither can the decrease in
melatonin be explained by increased concentrations of
gonadotrophin and sex steroids at puberty, since it has been
proved that GnRH-agonist therapy does not alter plasma
melatonin (Berga et al., 1989; Waldhauser et al., 1991).
These data suggest that the reduction in nocturnal serum
melatonin is not connected simply with an increase in body
mass, but is also temporally related to sexual maturation
(Waldhauser et al., 1991).
Conversely, some researchers, on the basis of experi-
ments using female Rhesus monkeys, postulate that elev-
ated nocturnal melatonin concentrations do not play a role
in the control of either the onset of puberty or ovulatory
function in adults (Wilson et al., 1992). In contrast to this
hypothesis, evidence from human pathological conditions
also suggests the suppressive role of high serum melatonin
on pubertal development, pulsatile secretion of GnRH and
ovarian function (Cavallo, 1993). Children with pre-
cocious puberty have been found to have lower nocturnal
serum concentrations of melatonin than age-matched pre-
pubertal children (Waldhauser et al., 1991), whereas
children with delayed puberty present higher nocturnal
melatonin concentrations than age-matched normal
children (Cohen et al., 1982). In pathologies characterized
by inactivity of the GnRH pulse generator, such as hypo-
thalamic amenorrhoea or anorexia nervosa, the amplitude
of nocturnal melatonin has been reported to be significantly
higher than in normal controls, with values similar to the
prepubertal ones (Berga et al., 1988; Brzezinski et al.,
1988; Tortosa et al., 1989).
Interestingly, research on rats suggests a possible influ-
ence of the maternal pineal during gestation on the gonadal
and genital development and function of offspring (Jarrige
and Boucher, 1992). However, investigations are needed to
evaluate this hypothesis in humans.
Melatonin and the hypothalamic–pituitary–ovarian axis
Data from human puberty lend support to the hypothesis
that the pineal exerts an inhibitory function on the repro-
ductive axis. The pineal suppressive role is also indicated
by melatonin administration tests. It has been reported that
long-term daily administration of melatonin, alone
(300 mg) or associated with norethisterone (0.75 mg),
induces in the fourth month of medication a significant
decrease in LH (with absence of the mid-cycle peak),
oestradiol and progesterone plasma concentrations.
Furthermore, a combination of 300 mg of melatonin with
0.15 mg of norethisterone or 75 mg of melatonin with
0.3 mg of norethisterone, administered for 21 days, has
also been reported to inhibit ovulation, suggesting an addi-
tive or synergic effect of the two hormones and the possi-
bility of a new contraceptive (Voordouw et al., 1992).
However, only scant data are available in humans,
especially with regard to where and how the pineal
suppressive role is exerted. There is evidence that the pin-
eal is involved in the control of the pulsatile secretion of LH
(Brzezinski et al., 1987). A negative relationship between
nocturnal serum melatonin and LH concentrations has
been documented at different pubertal stages (Waldhauser
et al., 1984). Interestingly, the influence of the season on

the ovulatory LH surge has been described (Testart et al.,
1982) and a role for melatonin in the timing of the LH surge
has also been suggested (Brzezinski et al., 1987). As yet,
however, it has not been clearly demonstrated in humans
whether melatonin exerts these effects by acting at the
hypothalamic level or directly at the pituitary level.
There is evidence to suggest that the inhibitory role of
melatonin is exerted at the hypothalamic level, influencing
the pulsatile secretion of GnRH. In patients with functional
hypothalamic amenorrhoea, whose main hormonal feature
is decreased GnRH/LH pulsatility, a significant increase in
the nocturnal peak amplitude and duration of melatonin has
been documented (Berga et al., 1988; Brzezinski et al.,
1988). In amenorrhoeic athletes, who have alterations of
the hypothalamic–pituitary–ovarian axis similar to those
observed in hypothalamic functional amenorrhoea, mela-
tonin secretion presents a higher nocturnal peak and a 2
hour delay of peak offset (Laughlin et al., 1991). In patients
with anorexia nervosa, also characterized by suppressed
hypothalamic pulsatile release of GnRH, enhanced diurnal
and nocturnal mean plasma melatonin values with anti-
cipation of nocturnal melatonin increase have been
reported (Tortosa et al., 1989). Since long-term administra-
tion of melatonin is also capable of inhibiting ovulation
(Voordouw et al., 1992), the nocturnal amplified melatonin
concentration in these conditions does not appear as an
epiphenomenon, although the mechanism of pathological
increase in melatonin remains to be elucidated.
Studies have been carried out to investigate the mechan-
ism by which melatonin can inhibit the hypothalamic
secretion of GnRH. Melatonin has been proposed to act by
directly suppressing the hypothalamic pulsatile secretion
of GnRH (Bittman et al., 1985). Conversely, it has been
suggested that this inhibition is mediated by a change in
dopaminergic and opioidergic activity (Rasmussen, 1993).
However, the mechanism by which melatonin inhibits
GnRH pulsatile release is not yet clear.
In rats, melatonin has been observed to inhibit the pitu-
itary response to LHRH (Martin et al., 1980; Vanecek and
Klein, 1992; Hattori et al., 1995). This has not been con-
firmed in humans (Weinberg et al., 1980; Brzezinsky and
Wurtman, 1988). In addition, an inhibin-like anti-gonado-
trophic activity associated with the protein–peptide
extracts of ovine pineal has been identified (Bhagat and
Duraiswami, 1992).
The influence of the pineal on reproductive function,
however, is not limited to the hypothalamic–pituitary level.
There is evidence for the existence of melatonin receptors
also in the testis and ovary of certain animals and of
humans (Cohen et al., 1978; Ayre and Pang, 1994). In
addition, the presence of melatonin has been demonstrated
The pineal gland and reproduction 231
in human pre-ovulatory follicular fluid at a concentration
significantly higher than in peripheral serum and with both
circadian and circannual variations (Ronnberg et al.,
1990). All of these data indicate the possibility of a direct
action of melatonin on the gonads. Furthermore, melatonin
has been reported to stimulate progesterone synthesis in
vitro by human corpus luteum cells (MacPhee et al., 1974)
and by granulosa cells luteinized in vitro (Webley and
Luck, 1985). Melatonin also enhances the stimulatory
effect of human chorionic gonadotrophin on progesterone
production by human granulosa lutein cells (Brzezinsky et
al., 1992). These studies therefore suggest that melatonin
may play a role in the modulation of luteal function and that
an abnormal melatonin concentration might result in
altered ovarian function. Data regarding melatonin influ-
ence on the human hypothalamic–pituitary–ovarian axis
are summarized in Table I.
In rats, melatonin has been found to increase serum pro-
lactin concentrations (Moreno et al., 1992). In women of
reproductive age a facilitatory role of melatonin in thyro-
trophin-releasing hormone-induced prolactin secretion has
been reported: this should be a sex-specific effect (Terzolo
et al., 1991). Conversely, no facilitatory function has been
observed in the response of FSH, LH or thyroid-stimulating
hormone to the respective releasing hormones or of cortisol
to adrenocorticotrophic hormone (Terzolo et al., 1991).
Melatonin and the menstrual cycle
Although considerable inter-individual differences in
plasma melatonin concentrations in humans have been
reported (Lerchl and Partsch, 1994), intra-individual vari-
ations seem to be small (Arendt, 1979). A daily rhythm in
serum melatonin concentrations can be observed in normal
women: diurnal melatonin concentrations are low (with
reported levels ranging from undetectable values to 25 pg/
ml = 108 pmol/l); a nocturnal rise starts at ∼9 p.m. and
reaches a peak at ∼3 a.m. (reported mean levels: 83 pg/ml =
358 pmol/l); a rapid decrease takes place between 5 a.m.
and 7 a.m. (Brzezinski et al., 1988).
With regard to an association between melatonin con-
centrations and the menstrual cycle, conflicting results
emerge from the literature. A few studies have reported an
increase in serum melatonin during the luteal phase, pre-
ceded by a mid-cycle hormonal decrease, and thus a role
for melatonin in the modulation of the menstrual cycle has
been suggested (Hariharasubramanian et al., 1984, 1986).
To the contrary, recent investigations have excluded a cor-
relation between serum melatonin concentrations and dif-
ferent phases of the menstrual cycle (Brzezinsky et al.,
1988; Berga and Yen, 1990). In particular, plasma mela-
tonin concentrations measured in four different phases of
232 V.Aleandri, V.Spina and A.Morini
the menstrual cycle (assessed by obtaining daily samples
for measurement of serum FSH, LH, oestradiol and pro-
gesterone) exhibited no consistent variation in circadian
pattern related to a specific menstrual phase. Therefore,
serum melatonin does not appear to be affected by fluctu-
ations in sex steroids during the menstrual cycle, and mela-
tonin secretion would not seem to be involved in the
modulation of menstrual cyclicity (Berga and Yen, 1990).
This hypothesis would appear to be confirmed by the find-
ing that the plasma melatonin concentrations do not seem
to be influenced by changes in sex hormone concentrations
related to pregnancy, ovulation induction with gonadotro-
phins and contraceptive use (Delfs et al., 1994). However,
according to another hypothesis, the lack of chronological
correlation between plasma ovarian hormones and melato-
nin concentrations does not mean that melatonin has no
role in modulation of the menstrual cycle (Brzezinski et al.,
1988). In fact, a chronological correlation between the
onset of the LH pre-ovulatory surge and the early morning
decrease in serum melatonin concentration has been
reported, suggesting a role for melatonin in the timing of
the mid-cycle LH surge (Brzezinski et al., 1987).
Evidence supporting melatonin regulation of the men-
strual function also emerges from pathology. Interestingly,
in women with amenorrhoea of hypothalamic origin, not
only a considerable increase in the nocturnal peak ampli-
tude but also prolonged melatonin secretion during the
daytime have been reported (Berga et al., 1988; Brzezinski
et al., 1988; Tortosa et al., 1989; Laughlin et al., 1991).
This suggests an alteration in the rhythm of melatonin
secretion. Importantly, the duration of melatonin secretion
has been found to represent a critical component of the
melatonin signal which elicits cyclic reproductive responses
in the hamster and sheep (Bartness et al., 1993). In addition,
menstrual cycle disorders are often associated with depres-
sion, which appears to be related to chronobiological
abnormalities and to be sensitive to phototherapy (Sack et
al., 1990). All of these data suggest that melatonin may
control menstrual cyclicity, and that this control is exerted
not only by its concentration but also by its secretion
rhythm. Moreover, these findings lend support to the
hypothesis that alterations in the circadian system may be
involved in the pathogenesis of menstrual irregularities.
This is also consistent with the finding of melatonin recep-
tors in the suprachiasmatic nuclei (Weaver et al., 1993).
Significantly, in women with a history of menstrual dis-
orders and anovulation, regularization of the cycle length
has been obtained by exposure to continuous low nocturnal
light for more than one cycle (Dewan et al., 1978). Hence,
due to the ability to phase-shift the circadian system
(Humlova and Illnerova, 1990; Deacon et al., 1994;
Dawson et al., 1995), the use of phototherapy or melatonin
in the therapeutic approach to non-organic menstrual
irregularities deserves to be more extensively tested.
Conclusion
The pineal gland appears to play an important role in the
neuroendocrine control of reproductive physiology. This is
well documented in seasonally breeding animals, in which
reproductive activity is clearly influenced by the seasonal
changes in the duration of day and night. Humans are not
seasonal breeders and, especially in western societies deeply
conditioned by progress, environmental impact is certainly
less important than in animals. Nevertheless, seasonal
trends have been demonstrated in human reproduction. In
humans the pineal gland also appears to play an important
role in the neuroendocrine control of sexual maturation and
of reproductive function, although many aspects remain to
be elucidated. The pineal seems to exert its hormonal effect
at different levels of the reproductive axis: at the hypotha-
lamic–pituitary level and directly at the gonadal level.
Furthermore, melatonin appears to increase prolactin
secretion. Although not all researchers agree, it has been
suggested that melatonin may be involved in the modula-
tion of menstrual cyclicity.
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Received on October 10, 1995; accepted on January 18, 1996