Reviews of Reproduction (1999) 4, 67–72

Inhibitory effect of melatonin on GnRH-induced LH release

Jiri Vanecek
Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague 4,
Czech Republic

Melatonin inhibits GnRH-induced release of LH and FSH from the neonatal, but not the adult,
rat anterior pituitary gland. This action of melatonin is mediated by the specific high-affinity
membrane-bound receptors that are absent in adult rats. The intracellular mechanism of
melatonin action involves a decrease in intracellular calcium [Ca2+]i in the gonadotrophs; mela-
tonin inhibits GnRH-induced Ca2+ release from endoplasmic reticulum as well as Ca2+ influx
through voltage-sensitive channels. Melatonin also inhibits GnRH-induced accumulation
of cAMP, which may result in the decreased influx of Ca2+, because cAMP, acting through
protein kinase A, stimulates Ca2+ influx into the gonadotrophs. This age-dependent effect
of melatonin on gonadotrophin release from the pituitary may be involved in the timing of
puberty.

An inhibitory effect of melatonin on GnRH-induced LH release
from the neonatal rat anterior pituitary gland was first de-
scribed by Martin and Klein (1976), who used cultured rat pitu-
itary gland as a bioassay system for testing antigonadotrophic
factors in the pineal gland. The neonatal tissue was selected be-
cause small, immature tissues generally survive well in organ
culture. The release of LH from gonadotrophs is low under
resting conditions and is not affected by melatonin (Martin and
Klein, 1976). The effect of melatonin on LH release has been
confirmed using dispersed pituitary cells in culture (Martin
et al., 1982; Vanecek and Klein, 1992a).
Melatonin inhibits the effects of GnRH in a dose-dependent
manner; a threshold concentration for inhibition of in vitro LH
release is about 10–10 mol l–1 and the maximal inhibition is seen
using concentrations of 10–8 to 10–7 mol l–1 (Fig. 1; Martin et al.,
1977). This value correlates with the physiological concen-
trations of melatonin (approximately 0.5 nmol l–1) found in rat
serum at night (Wilkinson et al., 1977; Illnerova et al., 1978). The
order of potency of the indoles is 2-iodomelatonin > melatonin
> 6-hydroxymelatonin > N-acetylserotonin > 5-methoxytrypt-
amine >> 5-hydroxytryptamine.
Although most studies of melatonin have investigated its
effect on LH release, melatonin also blocks GnRH-induced FSH
release (Martin and Sattler, 1982), probably acting directly on
gonadotrophs, because it suppresses LH release from an en-
riched gonadotroph fraction prepared from dispersed anterior
pituitary gland cells (Martin et al., 1982). Melatonin does not
affect the basal or releasing factor-induced release of other pitu-
itary gland hormones, that is, thyroid-stimulating hormone,
prolactin or growth hormone (Martin and Sattler, 1982).
The inhibitory effects of melatonin on LH and FSH release
are age-dependent, as demonstrated first, in 1977, using cul-
tured pituitary glands and then confirmed using dispersed cells
(Martin and Sattler, 1979). In 4- to 8-day-old rats, melatonin
inhibits GnRH-induced LH release by about 50–60%, but, after
10 days of age, this inhibitory action begins to decrease and
is undetectable after 15 days of age. These developmental
changes correlate with a postnatal decrease in melatonin
© 1999 Journals of Reproduction and Fertility
1359-6004/99 $15.00
receptor density in the anterior pituitary gland (see Fig. 2 and
below; Vanecek, 1988a).
The inhibitory effect of melatonin on GnRH-induced gon-
adotrophin release may not be limited to rats. Our preliminary
data indicate that melatonin inhibits GnRH-induced LH release
from the cultured pituitary cells in neonatal Siberian hamsters
(J. Vanecek and M. Masson-Pevet, unpublished). However,
melatonin has no effect on GnRH-induced LH response in the
pituitary of neonatal Syrian hamsters (Bacon et al., 1981).
Melatonin receptors
Melatonin receptor in the anterior pituitary gland has been in-
vestigated using 125I-melatonin binding. The receptor has a
high affinity (Kd ~ 10–11 mol l–1) and is located in the plasma
membrane (Vanecek et al., 1987; Vanecek, 1988b). Using
RT–PCR, Mel1a receptor mRNA has been identified in the neo-
natal rat pituitary (J. Vanecek, S. Coon and D. C. Klein, un-
published). Melatonin receptor is present in the pars distalis
and pars tuberalis of the rat pituitary (Vanecek, 1988a; Williams
and Morgan, 1988; Williams et al., 1991). In the rat pars distalis,
the melatonin receptor density is age-dependent (Fig. 2). On
embryonic day 20 and postnatal day 1, the density is about
30 fmol mg–1 protein but by postnatal day 30; it decreases
tenfold, that is, below 3 fmol mg–1 protein (Vanecek, 1988a).
Similar developmental changes in melatonin receptor density
have been described in the pars distalis of the Syrian hamster
(Vanecek and Kosar, 1994). The concentration of melatonin re-
ceptor in the pars tuberalis does not change significantly as
neonatal rats develop into adults.
The factor(s) inducing the decrease in melatonin receptor
concentration in the pars distalis between birth and 15 days of
age are unknown. The decrease may be due to the decreased
expression of the melatonin receptor, because the concentration
of Mel1a mRNA in the rat pituitary decreases markedly be-
tween day 1 and day 30 (J. Vanecek, S. Coon and D. C. Klein,
unpublished). The melatonin receptor density in the pars dis-
talis of the pituitary increases twofold in postpubertal male
68 J. Vanecek

(a) (b) (c)

120 GnRH (2 nmol l –1) 120 Forskolin (2 µmol l –1) 120 GnRH (2 nmol l –1)
LH release (percentage GnRH)

100 100 100

cAMP (percentage forskolin)

Calcium (percentage GnRH)

80 80 80

60 60 60

40 Control 40 40
Control
20 20 Control 20

0 0 0

0 –12 –11 –10 –9 –8 –7 0 –12 –11 –10 –9 –8 –7 0 –11 –10 –9 –8 –7

Melatonin (mol l –1) Melatonin (mol l –1) Melatonin (mol l –1)

Fig. 1. Dose-dependent effects of melatonin in cultured pituitary cells from neonatal rats. Melatonin inhibits (a) GnRH-induced LH release,
(b) forskolin-induced cAMP accumulation, and (c) GnRH-induced intracellular free calcium. Each point represents the mean (± SEM) from at
least three independent cultures.

rats 2–4 weeks after castration (Vanecek et al., 1990). Melatonin G-proteins
receptor density may increase as a consequence of removal of
Melatonin receptor is coupled to GTP-binding protein. In
gonadal steroids. In support of this view, an inhibitory effect
the presence of GTP or non-hydrolysable GTP derivatives, the
of gonadal steroids on 125I-melatonin binding in caudal and
affinity of the melatonin receptor for 125I-melatonin is de-
cerebral arteries has been shown (Seltzer et al., 1992). In rats,
125I-melatonin binding to the arteries is highest at dioestrus, creased (Morgan et al., 1989). The effects of melatonin in the
pituitary gland, including the inhibition of LH release and
when circulating oestrogen concentrations are low whereas,
the effects on second messengers, are abolished after pre-
at pro-oestrus and oestrus, when oestrogen concentrations
incubation with pertussis toxin (Vanecek and Klein, 1992a; see
are high, melatonin binding capacity decreases. Therefore, it
below). This finding indicates that the receptor is coupled to
is possible that the increasing concentration of gonadal
the G-protein belonging to the Gi family which consists of
steroids in prepubertal rats causes the decrease of melatonin
five protein species. It is not clear which of these G proteins is
receptor expression in the anterior pituitary after 10 days of
involved in the transduction of the melatonin signal.
age.
The postcastration increase of GnRH secretion, which in-
creases the number of gonadotrophs, is another factor that Second messengers
may account for the increase of the melatonin receptor density
Melatonin affects several intracellular messengers in the pitu-
after castration (Hellbaum et al., 1961; Sarkar and Fink, 1980;
itary cells in an inhibitory fashion (Fig. 1). It inhibits the in-
Clayton and Catt, 1981). Since available data indicate that mela-
crease in intracellular calcium concentration ([Ca2+]i), and the
tonin receptor is located on gonadotrophs (Martin and Sattler,
cAMP- and cGMP-accumulation induced by GnRH (Vanecek
1982), a GnRH-induced increase in the number of gonado-
and Vollrath, 1989; Vanecek and Klein, 1992a).
trophs may be responsible for the postcastration increase in
melatonin receptor concentration in the pituitary. This mechan-
Calcium
ism may also explain the developmental changes of the pitu-
itary melatonin receptor density, since the concentration of GnRH-induced increase of [Ca2+]i is the primary signal for
GnRH in amniotic fluid increases approximately tenfold be- LH release from gonadotrophs (Conn et al., 1987; Tasaka et al.,
tween embryonic day (E)12 and E16 (Jennes, 1990), which cor- 1988). Melatonin inhibits the GnRH-induced increase in [Ca2+]i,
responds with the time (E15) when the pituitary melatonin which may account for the inhibitory effect of melatonin on LH
receptor is first detected (Williams et al., 1991). After birth, the release (Fig. 1; Vanecek and Klein, 1992a; Slanar et al. 1997).
pars distalis is exposed to an abrupt decrease in GnRH, which GnRH induces [Ca2+]i increase by two mechanisms: initially, it
may cause the postnatal decrease in melatonin binding site induces Ca2+ release from IP3-sensitive stores, after which is a
density (Vanecek, 1988a). Ca2+ influx through voltage-sensitive channels (Tasaka et al.,
 Effect of melatonin on LH release 69

1988). The available data indicate that melatonin may inhibit

both pathways.
(a)
In Ca2+-free medium, GnRH induces an increase in [Ca2+]i 35
exclusively by mobilization from intracellular stores. In most of
the neonatal rat gonadotrophs cultured in Ca2+-free medium,
30
the GnRH-induced [Ca2+]i increase is transient, with a spike
followed by a rapid decrease to basal concentrations. In the

Bmax (fmol mg –1 protein)

presence of melatonin, the Ca2+ spike is inhibited in about 25
30% of the gonadotrophs (Slanar et al., 1997).
The inhibitory action of melatonin on GnRH-induced [Ca2+]i 20
increase has also been studied by electrophysiological methods
(Zemkova and Vanecek, 1997). The GnRH-induced increase 15
in [Ca2+]i activates apamine-sensitive Ca2+-activated K+ (Kca)
channels (Kukuljan et al., 1992; Tse and Hille, 1992). Melatonin 10
inhibits GnRH-induced K+ currents and this effect is seen
also in Ca2+-free medium (Zemkova and Vanecek, 1997). This
finding is in agreement with the hypothesis that melatonin 5
inhibits GnRH-induced Ca2+ mobilization from intracellular
stores. 0
Melatonin may block the GnRH-induced [Ca2+]i increase by 0 5 10 15 20 25 30
inhibiting GnRH-induced phospholipase C activity (Fig. 3; Age (days)
Vanecek and Vollrath, 1990; V. Pelisek and J. Vanecek, un-
published). Phospholipase C metabolizes phosphatidylinositol (b)
bisphosphate (PIP2) into diacylglycerol and inositol trisphos- 60
phate (IP3) which, in turn, induces the release of Ca2+ from the
Percentage LH inhibition by melatonin

endoplasmic reticulum (Berridge, 1993). Melatonin inhibits 50

the GnRH-induced formation of diacylglycerol in the gon-
adotrophs (Vanecek and Vollrath, 1990) and preliminary ob- 40
servations indicate that it also inhibits GnRH-induced IP3
accumulation (V. Pelisek and J. Vanecek, unpublished).
30
Besides Ca2+ mobilization, melatonin also inhibits Ca2+ in-
flux (Vanecek and Klein, 1992a,b). In neonatal rat gonadotrophs
cultured in Ca2+-supplemented medium, the GnRH-induced 20
Ca2+ spike is followed either by a sustained plateau or by
calcium oscillations (Tomic et al., 1994; Slanar et al., 1997). 10
Melatonin added after the GnRH-induced Ca2+ spike decreases
[Ca2+]i in about 50% of gonadotrophs. The inhibitors of voltage- 0
sensitive Ca2+ channels, verapamil and nifedipine, mimic this
effect of melatonin. This effect is not observed in Ca2+-free
medium when melatonin is added after the GnRH-induced 0 5 10 15 20 25 30
spike. These observations indicate that melatonin inhibits Ca2+
influx through voltage-sensitive channels. The action of mela- Age (days)
tonin may involve hyperpolarization of the plasma membrane
(Fig. 3; Vanecek and Klein, 1992b). Melatonin induces hyper-
polarization probably by inhibiting Na+ influx into gonado- Fig. 2. Age-dependent changes of melatonin-binding site density
trophs because, in Na+-free medium, it loses the capacity in the rat pituitary (a; Bmax) and capacity of melatonin to inhibit
to affect membrane potential (Vanecek and Klein, 1992b). GnRH-induced LH release from the cultured pituitary cells (b).
Moreover, preliminary studies using fluorescent indicator (Data from Martin and Sattler, 1979; Vanecek, 1988a.)
of intracellular Na+ indicate that melatonin inhibits the
GnRH-induced increase of [Na+]i in neonatal rat gonadotrophs
(O. Slanar and J. Vanecek, unpublished).
Cyclic nucleotides
Hyperpolarization closes the voltage-sensitive channels and
inhibits Ca2+ influx. This effect of melatonin may be of primary Melatonin also inhibits the cAMP accumulation induced
importance in the mechanism responsible for its inhibition of by GnRH or forskolin in cultured anterior pituitary glands
GnRH-induced LH release. In the presence of the L-channel (Vanecek and Vollrath, 1989). Later dispersed cell cultures
agonist, Bay K, the inhibitory effect of melatonin on LH release were used to study the inhibitory effect of melatonin and its
is markedly reduced. Moreover, an inhibitor of voltage- derivatives on forskolin-induced cAMP accumulation, because
sensitive Ca2+ channels, nifedipine, also inhibits GnRH-induced GnRH does not consistently increase cAMP in dispersed pitu-
LH, mimicking the action of melatonin in a non-additive itary cells (Fig. 1b; Vanecek, 1995). The effect of melatonin
manner. is dose-dependent, and mediated by pertussis toxin-sensitive
70 J. Vanecek

AC cAMP
Mel CNG
Rec
PKA
ER Na+
pump
Ca2+ Ca2+
VSCC
GnRH
Rec
Ca2+
InsP3
PLC
Ca2+
KCa
Mel Depolarization
Rec K+

Na+
Na/Ca
exchange VSSC VSCC

Ca2+ Na+ Ca2+

Fig. 3. Proposed mechanisms of inhibition by melatonin of GnRH-induced LH release from the neonatal rat gonadotroph. Melatonin may
inhibit GnRH-induced Ca2+ mobilization by inhibiting phospholipase C activity and inositol trisphosphate (IP3) formation. Inhibition of Ca2+
influx by melatonin may be due to hyperpolarization of plasma membrane, which closes voltage-sensitive Ca2+ channels. Hyperpolarization
may be caused by the inhibitory effect of melatonin on Na+ influx via an Na+–Ca2+ exchanger or via cyclic nucleotide-gated channels.
Alternatively, inhibition of adenylyl cyclase and decrease of cAMP by melatonin may decrease the permeability of the voltage-regulated
Ca2+-channels by preventing phosphorylation by cAMP-dependent kinase. AC, adenylyl cyclase; CNG, cyclic nucleotide-gated channel;
ER, endoplasmic reticulum; GnRH Rec, GnRH receptor; KCa, Ca2+-sensitive K+ channel; Mel Rec, melatonin receptor; PKA, cAMP-dependent
kinase; PLC, phospholipase C; VSCC, voltage-sensitive Ca2+ channel; VSSC, voltage-sensitive Na+ channel; , stimulatory input;
, inhibitory input.

G protein. The inhibitory effect of melatonin on cAMP accumu-
lation is probably mediated by a mechanism different from that
mediating the decrease of [Ca2+]i. In Na+-free medium, mela-
tonin loses its capacity to decrease GnRH-induced [Ca2+]i but it
retains the capacity to inhibit GnRH-induced cAMP accumu-
lation in the cultured pituitaries of neonatal rats (Vanecek,
1995). The melatonin effect is preserved in the presence of
high concentration of phosphodiesterase inhibitor 3-isobutyl-1-
methylxanthine, which indicates that melatonin does not act
via phosphodiesterase but inhibits adenylyl cyclase (Fig. 3).
The melatonin-induced decrease in cAMP is not of primary
importance for the inhibition of LH release. Even in the
presence of the permeable cAMP derivative, 8-bromo-cAMP,
melatonin inhibits the GnRH-induced LH release (Vanecek
and Klein, 1995). Nevertheless, cAMP may be involved in
transduction of the melatonin signal into gonadotrophs.
Preliminary data indicate that cAMP acting via protein
kinase A may stimulate Ca2+ influx in the gonadotrophs
(Fig. 3; O. Slanar and J. Vanecek, unpublished). A similar
mechanism has been found in clonal αT3-1 gonadotrophs
in which activation of protein kinase A stimulates Ca2+ influx
through dihydropyridine-sensitive channels (Hezareh et al.,
1997).
Melatonin also inhibits a GnRH-induced increase in cGMP
accumulation in the pituitary gland (Vanecek and Vollrath,
1989). This effect of melatonin is dose-dependent, with the
maximum inhibition at 10–9 mol l–1. The inhibitory effect of
melatonin may be mediated by a decrease of [Ca2+]i, since
cGMP synthesis may be stimulated by calcium (Wong and
Garbers, 1992; Gorczyca et al., 1995). The GnRH-induced in-
crease in cGMP may be involved in the control of LH release
but its precise role is uncertain (Naor, 1990).
Transcription factors
GnRH regulates not only the release but also the synthesis of
LH and FSH in the pituitary (Starzec et al., 1986). The addition
of GnRH to the cultured pituitary cells increases the messenger
RNAs for c-fos, c-jun and jun B (Cesnjaj et al., 1994). This in-
crease is rapid and transient, with the concentration of these
 Effect of melatonin on LH release
transcription factors reaching peak values 30 min after addition
of GnRH and then gradually decreasing.
In neonatal rat pituitary cells, GnRH increases c-Fos im-
munoreactivity and the action of GnRH is inhibited by mela-
tonin (Sumova and Vanecek, 1997). Melatonin suppression of
GnRH-induced early gene expression suggests that the indole
may regulate not only the release of LH and FSH but also the
synthesis of these hormones.
Function of the inhibitory effect of melatonin on
GnRH-induced gonadotrophin release
The most important role of melatonin in mammals is the regu-
lation of seasonal rhythms (Underwood and Goldman, 1987).
Photoperiod drives seasonal breeding cycles in many mam-
malian species. Nocturnal secretion of melatonin from the
pineal gland is prolonged in animals kept on short photo-
periods and the duration of the melatonin pulse regulates the
reproductive functions. The effects of melatonin on reproduc-
tion in adult animals are probably not mediated by the pars
distalis of the pituitary, but through the mediobasal hypothala-
mus and pars tuberalis (Lincoln and Clarke, 1994; Maywood
and Hastings, 1995).
The physiological significance of the inhibitory melatonin
effects on GnRH-induced gonadotrophin release from the pitu-
itary of neonatal rats is not clear. It is possible that melatonin
mediates the photoperiodic regulation of the timing of puberty.
Adult laboratory rats are not photoperiodic, presumably be-
cause constant laboratory conditions remove the necessity for
seasonal adaptations or as a result of artificial selection against
seasonal breeding. However, prepubertal rats reared from birth
on short photoperiods have smaller reproductive organs than
those kept on long photoperiods (Vanecek and Illnerova, 1985).
Although a clearly defined rhythm of pineal melatonin concen-
tration starts from about 8 days of age (Tamarkin et al., 1980;
Pelisek et al., 1994), maternal melatonin may carry the photo-
periodic message to the fetuses and neonates. Melatonin crosses
the placental barrier freely and is also secreted into the milk
(Klein, 1972; Reppert and Klein, 1978; Illnerova et al., 1993).
Melatonin may exert the inhibitory effect on onset of
puberty, at least partially, at the pituitary by inhibiting the
GnRH-induced gonadotrophin release. The removal of this
inhibitory input due to the decrease of the melatonin receptors
may be one of the events initiating puberty. It is not clear why
rats have photoperiodically regulated puberty when the adults
are not seasonal breeders, but it may be that the regulation of
puberty is a remnant of the significant photoperiodic regu-
lations existing in wild rats. In Siberian hamsters, in which
photoperiod has marked effect on the timing of puberty, mela-
tonin inhibits GnRH-induced LH release from the neonatal
pituitary cells, but this effect has not been found in Syrian
hamsters, in which the timing of puberty is not sensitive to
photoperiod (Hoffmann, 1978; Bacon, 1981; Sisk and Turek,
1983; Yellon and Goldman, 1984; Cherry 1987; J. Vanecek and
M. Masson-Pevet, unpublished).
This work was supported by the grant number 309/97/0513 from
the Grant Agency of the Czech Republic and the grant number
A5011705 from the Internal Grant Agency of the Academy of Sciences
of the Czech Republic.
71
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