Download Neuroendocrine regulation of GnRH release and expression of

Vol. 10, No. 2
85
REVIEW
Neuroendocrine regulation of GnRH release
and expression of GnRH and GnRH receptor
genes in the hypothalamus-pituitary unit
in different physiological states
Magdalena Ciechanowska1, Magdalena Łapot, Krystyna Mateusiak,
Franciszek Przekop
The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy
of Sciences, Jabłonna, Poland
Received: 31 July 2009; accepted: 17 June 2010
SUMMARY
This review is focused on the relationship between neuroendocrine regulation of GnRH/LH secretion and the expression of GnRH and GnRH receptor
(GnRHR) genes in the hypothalamic-pituitary unit during different physiological states of animals and under stress. Moreover, the involvement of
hypothalamic GABA-ergic, β-endorphinergic, CRH-ergic, noradrenergic,
dopaminergic and GnRH-ergic systems in the regulation of expression of
the GnRH and GnRHR genes as well as secretion of GnRH/LH is analyzed.
It appears that the neural mechanisms controlling GnRH gene expression in
different physiological states may be distinct from those regulating GnRH/
Corresponding autor: The Kielanowski Institute of Animal Physiology and Nutrition, Polish
Academy of Sciences, 05-110 Jabłonna, 3 Instytucka Street, Poland; e-mail: m.ciechanowska@
ifzz.pan.pl
1
Copyright © 2010 by the Society for Biology of Reproduction
86
Regulation of GnRH secretion
LH release. The hypothalamic GnRHR gene is probably located in different
neural systems and may act in a specific way on GnRH gene expression and
GnRH release. Reproductive Biology 2010 10 2: 85-124.
Key words: ewe, hypothalamus, GnRH mRNA, GnRHR mRNA, LH
INTRODUCTION
Gonadotropin cells in the anterior pituitary gland are regulated by the release of GnRH from the hypothalamus into the primarily portal capillaries
in the median eminence (ME) and its delivery to the target via the hypophyseal portal vein [176]. The GnRH cells in the central nervous system
are not segregated into neural clusters but appear as a loose network spred
through many cytoarchitectonic structures. In most species, GnRH cells
form a loose continuum from the diagonal band of Broca and more dorsal
septal areas, to the bed nucleus of the stria terminalis and diencephalic
areas. Also in this continuum there are cells lying dorsal to and within the
supraoptic nucleus (SOP).
GnRH release is controlled by numerous stimulatory and inhibitory
factors as well as factors with biphasic effects on GnRH neurons [64, 201].
After the isolation and sequencing of porcine and ovine GnRHs, it appeared
that these peptides isolated from several classes of vertebrates showed
multiple substitutions in their sequence when compared with pig or sheep
GnRH [66, 117, 125, 144, 172]. Until now, more than a dozen isoforms of
GnRH sharing 10-50% amino acid identity has been found in vertebrates.
The conservation of the length of these peptides, NH2 terminus and COOH
terminus indicates that these features are critically important for receptor
binding and activation.
It is generally thought that most vertebrates possess at least two, and
usually three, forms of GnRH which differ in their amino acid sequence,
localizations and embryonic origins [21]. The most ubiquitous is chicken
GnRH II which is the evolutionary conserved member of the GnRH peptide family. Its form in mammals differs from GnRH I by three amino acid
residues at position 5, 7, 8 [21, 117]. It has been shown that the biological
Ciechanowska et al
87
functions of GnRH I and GnRH II are different. Whereas GnRH I plays
a pivotal role in the regulation of reproduction by stimulating the pituitary
release of LH and FSH, GnRH II participates mainly in the control of
puberty, reproductive behavior, feeding and energy balance [21]. Growing
evidence shows that both GnRH I and GnRH II are potentially important
autocrine/paracrine regulators in some extrapituitary compartments [21].
The actions of GnRHs are mediated by the GnRH receptors (GnRHR)
which belong to a G protein-couple receptor (GPCR) subfamily. The GnRHR
cDNA encodes a 327-328 amino acid protein with seven putative membranespanning domains characteristic for GPCR [86, 93, 117, 118, 182]. Only
one conventional GnRH receptor subtype (GnRH-IR) uniquely lacking
a carboxyl-terminal tail has been found in mammals [21]. The GnRH-IR
lacks a typical intracellular carboxyl terminus, making it one of the smallest
receptors with the seven-transmembrane segment motive.
Recent cloning of the GnRH-II receptor subtype in non-human primates
revealed that it is structurally and functionally distinct from the mammalian
GnRH-IR [22]. The most striking difference between these receptor subtypes is the relation of a presence of 56-residue cytoplasmatic tail domain
at the carboxyl-terminus of GnRH-IIR with its absence in GnRH-IR [21,
66, 144]. The presence of a cytoplasmatic tail domain alters receptor trafficking dynamics. Indeed recent studies have demonstrated that the marmoset GnRH-IIR undergoes a more rapid agonist-induced internalization
compared with the human GnRH-IR [144]. In vitro GnRH I and GnRH II
can bind with different affinities to GnRH receptor isoforms. The GnRHIR binds GnRH I with higher affi nity than GnRH-IIR, and GnRH-IIR
has higher affinities for GnRH II than for GnRH I [66, 117, 125]. Other
important sequence differences between receptor subtypes occur in the
extracellular, transmembrane and cytoplasmic loop domains. In GnRHIIR receptors, the N-terminal domain is two-residues longer and more
negatively charged than the GnRH-IR [66]. Excellent reviews have been
written on these subjects, to which the reader can refer for a more description of GnRH I and GnRH II interaction with GnRH-R I and GnRH-R II
and their physiological significance in the physiology of reproduction [21,
66, 117, 118, 144].
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Regulation of GnRH secretion
REGULATION OF GNRH/LH RELEASE AND EXPRESSION
OF GNRH AND GNRHR GENES DURING THE ESTROUS
CYCLE AND ANESTROUS PERIOD IN EWES
The regulation of GnRH secretion in mammals is associated with complex
interplay among excitatory and inhibitory neurotransmitter- and neurohormone -systems activity within the hypothalamus (fig. 1). The activities of
these systems and their functions in the control of GnRH release from the
hypothalamus during the estrous cycle depend mainly upon estrogen and
progesterone (P4) secretion [51, 71, 94, 156]. Both estradiol (E2) and P4 exert
positive and negative action on GnRH secretion. In the interval between
luteolysis and preovulatory gonadotropin surges in ewes, E2 exerts a dosedependent suppression of GnRH from the hypothalamus [37]. This effect is
mediated by a reduction in the GnRH pulse size and occurs despite a stimulatory action on GnRH pulse frequency [50]. Whereas both E2 and P4 inhibit
episodic GnRH release, high circulating levels of E2 during preovulatory
gonadotropin surge stimulate GnRH output [18, 51].
The ability of E2 to activate GnRH cells in the hypothalamus in ewes is
affected by P4 through the temporal relationship between E2 and P4 exposure. Indeed, in the natural estrous cycle, the preovulatory surge of GnRH
is stimulated by elevated E2 secretion during the follicular phase in which P4
concentration is low. In contrast, increases in E2 secretion that accompany
follicular growth during the luteal phase are unable to stimulate GnRH release despite being of sufficient magnitude, due to the presence of enhanced
P4 concentration. However, exposure to P4 prior to an independent increase of
E2, which occurs during the follicular phase, augments GnRH surge in ewes
[51]. Progesterone by itself has not been shown to inhibit GnRH secretion
consistently in ovariectomized ewes, and it has been suggested that E2 is
necessary to sensitize the neuroendocrine axis to negative feedback action
of progesterone [156]. It has also been shown that the circulating level of
E2 is a regulator of physiological synaptic plasticity in the arcuate nucleus
(ARC) in rats [128]. In the late follicular phase of the estrous cycle the level
of E2 begins to rise resulting in both the inhibition of GnRH release and
sensitization of the pituitary gonadotrops to GnRH. It has been documented
Ciechanowska et al
89
5 -HT
HT
?
ER
NA/NPY
A1
ER
NA
A2
GABA
DA
CRH
PVN
DA
NPY
β-END
Figure 1. Afferent inputs of some neural systems to GnRH neurons in the preoptic
area; stem brain nuclei: A1, A2; nucleus arcuatus: ARC; corticotropin neurons:
CRH; dopamine neurons: DA; estradiol receptors: ER; gamma-aminobutyric
acid neurons: GABA; serotonine neurons: 5-HT; noradrenaline neurons: NA;
noradrenaline and neuropeptide Y neurons: NA/NPY; neuropeptide Y neurons
of ventromedial hypothalamus: NPY; β-endorphin: β-END; preoptic area: POA;
periventricular nucleus: PVN; ventromedial nucleus: VM; triangle: synapse; rectangle: close apposition; circle: nerve terminals.
that the abrupt and exquisitely timed release of GnRH at the peak of circulating estrogen in rats follows the disruption of inhibitory synapses in the
ARC that have been supporting the decrease of GnRH/gonadotropins release
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Regulation of GnRH secretion
during increasing pituitary sensitization to GnRH [128]. The estrogen with
GnRH regulates GnRH receptor activity in the anterior pituitary gland and
LH release in ewes [200].
On the other hand, GnRH/LH may regulate estrogen level which suggests considerable crosstalk between these two processes [128]. In ewes, E2
enhances GnRH-mediated release of LH from the pituitary gland during the
breeding season but not during anestrus or the period of transition into or
out of the breeding season [126]. However, in anestrous ewes treatment with
E2 but not P4 decreased pituitary LHβ mRNA in the hypothalamic-pituitary
disconnected animals [42]. In cycling ewes, P4 suppresses GnRH-R gene expression in the anterior pituitary gland [200]. However, the mechanism of P4
inhibitory action on the expression of GnRHR gene in the anterior pituitary
gland has not been fully recognized. There is evidence that P4 negatively
influences GnRHR gene expression through E2 as well as GnRH receptor
mechanism on gonadotropin cells. Since E2 affects its target cells via intracellular receptors and GnRH binds to receptors on the plasma membrane
of gonadotropic cells, P4 is assumed to affect GnRHR biosynthesis through
different cellular mechanisms [200].
The numerous studies on rats have also documented that E2 [11, 146, 161,
164, 196] and P4 [23, 97], in different physiological states and experimental
conditions, may increase or decrease GnRH gene expression in the hypothalamus. In the ovariectomized progesterone-estradiol treated ewes, GnRH/LH
release was not closely associated with the GnRH mRNA level suggesting
that the role of E2 in the neuroendocrine mechanism controlling GnRH gene
expression in the hypothalamus is distinct from that regulating GnRH release
[70]. Progesterone displays an exclusive regulatory influence on GnRH release
from the hypothalamus in ewes but has no effect on GnRH gene expression
in these species [163]. On the other hand, P4 seems to decrease GnRH gene
expression in cows [205]. The effects of ovarian steroids on the expression
of GnRH gene in the hypothalamus may be species-specific.
The experiments on the relationship between the GnRH mRNA level
in the hypothalamus and LH secretion in sheep have answered the question
to what extent the patterns of LH secretion in various physiological states
are related with GnRH gene expression [25, 27, 111]. It has been shown that
Ciechanowska et al
91
GnRH mRNA level in the entire hypothalamus of anestrous ewes was significantly lower than in the follicular and/or luteal phase animals (fig. 2). The
low GnRH gene expression in the hypothalamus of anestrous ewes may be
responsible for the decrease in GnRH biosynthesis and release as well as the
non-ovulatory state of ewes during a long photoperiod. It is worth noting,
that the level of GnRH mRNA in the hypothalamus is the net result of the
transcriptional activities of the GnRH gene, the degradation of transcriptional
product and the utilization of cytoplasmic GnRH mRNA in the biosynthesis
of GnRH. Thus the GnRH mRNA level may not reflect a clear relationship
between the transcriptional activity of GnRH gene with GnRH release.
Similarly to GnRH gene expression, the GnRHR mRNA level in the
hypothalamic-pituitary axis (fig. 2) of anestrous ewes is lower than in the
follicular and/or luteal phase female [25, 27, 111]. Several experiments on
rats have documented that the estrogen and P4 affect the GnRHR gene expression in the hypothalamus and the anterior pituitary gland, but their role
in rats may be different [84, 174]. In the anterior pituitary glands of rats [12,
208] and ewes [1, 100, 199, 200], E2 increases GnRHR gene expression, but
P4 suppresses GnRHR mRNA level [199, 200]. The stimulatory effect of
GnRH on GnRHR gene expression in the anterior pituitary gland in female
rats [12, 87, 109, 199, 200] and sheep [100, 200] is markedly enhanced by E2.
Homologous up – [12, 87, 109, 199, 208] or down – [1, 22, 166, 200, 207] regulation of GnRHR gene expression by GnRH in the anterior pituitary gland
depends to a high degree on the mode of treatment (continuous vs. pulsatile)
and concentration (high vs. low) of GnRH. The physiological significance of
GnRHR mRNA in the hypothalamus for GnRH gene expression and GnRH
release still remains not well understood. The results obtained on rats [84,
174] and sheep [26] suggest that GnRHR mRNA in the hypothalamus may
be involved in the control of GnRH release from the GnRH nerve terminals
as well as GnRH gene expression in the preoptic area (POA).
The fact that the GnRH neurons in the hypothalamus have a few or
no steroid receptors [75, 76, 103] has lead to the conclusion that E2 and P4
affect GnRH cell activity primarily via the steroid-receptive inter-neural
systems in the hypothalamus. Among the number of neural systems in the
hypothalamus affecting directly and/or indirectly GnRH activity, the no-
Regulation of GnRH secretion
92
2
A
Anestrous
GnRH/GAPDH (arbitrary units)
Luteal phase
Follicular phase
1,5
1
**
**
0,5
2
**
*
0
GnRH/GAPDH (arbitrary units)
**
AH
POA
**
VM
B
***
1,5
***
1
0,5
0
**
**
POA
**
AH
**
VM
**
**
SME
AP
Figure 2. GnRH (A) and GnRH receptor (GnRHR) mRNA (B) levels (mean±SEM)
in the hypothalamic-pituitary unit of anestrous, luteal and follicular phase ewes
(n=6). GnRH and GnRHR mRNA levels are presented as GnRH or GnRHR mRNA/
GAPDH mRNA ratio where GAPDH (glyceraldehyde 3-phosphate dehydrogenase)
is a reference gene. The significance of differences in the mRNA levels among groups
was assessed by one-way ANOVA followed by Tukey’s test, asterisks depict differences between anestrous and luteal or follicular phase ewes; *p≤ 0.05, **p≤ 0.01,
***p≤ 0.001; preoptic area: POA; anterior hypothalamus: AH; ventromedial hypothalamus: VM; stalk/median eminence: SME; anterior pituitary gland: AP.
Ciechanowska et al
93
radrenergic cells from the brain steam [43, 75, 171], GABA-ergic neurons
from the POA [43, 75] and β-endorphin perikarya from the ARC [29, 43,
75] are best recognized in synchronizing the firing of different groups of
GnRH neurons in the hypothalamus.
All noradrenergic cells from the A1 and A2 groups (nuclei of the brain
stem) in rats project axons to the POA and synapse with GnRH perikarya
and may directly stimulate GnRH release through α1 receptors located on
the GnRH cells [43, 75]. The location and exact targets of noradrenergic
neurons that affect GnRH secretion at the GnRH nerve terminals within
the ME are unknown [43, 75].
Axons from noradrenergic cells also activate GABA perikarya in the
POA to suppress GnRH secretion [43]. In the luteal phase ewes, P4 increases
GABA-ergic activity and decreases GnRH pulse frequency through the
GABA-ergic system [43]. During the early follicular phase, the period of
declining P4 secretion, estradiol inhibits the autoinhibitory system of GABA
cells, so, the increased GABA concentrations are maintained and suppress
GnRH/LH release [43]. Prolonged secretion of E2 during the follicular phase
leads to an increase in the stimulatory influence of noradrenaline (NA) on
GnRH cells in the POA with a concomitant suppression of GABA output in
this structure. The inhibitory influence of GABA on GnRH release in the
follicular phase ewes occurs through GABAA receptors, whose activation by
muscimol (agonist of GABAA receptors) decreases GnRH/LH release [26].
The GnRH perikarya in the POA are also under the inhibitory influence
of opioid neurons from the ARC [43, 179, 189]. Indeed, the opioid perikarya
project axons to the POA and synapse directly with GnRH cells [43].
Opioid neurons also synapse with NA interneurons in the POA [43, 179].
There is good evidence of a presynaptic inhibition of noradrenaline release
by β-endorphin in the POA of the rat [14, 41, 92, 168] and sheep [96].
The estrogen-induced decrease in tonic input of opioids on noradrenergic
neurons may further contribute to the elevation of preoptic noradrenaline
concentration and stimulate GnRH surge. This data indicate that noradrenergic neurons projecting to the vicinity of the GnRH cells are likely to be
stimulated directly by estrogen and in association with reduced presynaptic
opioid restraint, are responsible for the increased noradrenaline output within
94
Regulation of GnRH secretion
the POA [75]. It is interesting that a decrease in opioid activity just prior
to the LH surge occurs synchronously with the uncoupling of NA influence on GABA cells in the POA [43]. In rats, opioids restrain stimulatory
catecholaminergic, glutaminergic and nitric oxide inputs and enhance the
inhibitory action of GABA on GnRH neurons [52].
The presented results have shown that the activity of GABA and GnRH
perikarya in the POA are modulated by brain stem noradrenergic neurons in
response to a change in estrogen and P4 secretion. The estradiol-induced increase
of GnRH mRNA in the POA in rats is blocked by pretreatment with α-adrenergic
receptor antagonist suggesting that the noradrenergic system in the hypothalamus is involved in the regulation of GnRH gene expression and biosynthesis [75,
108]. Similarly, the suppression of noradrenergic neurotransmission significantly
reduces GnRH mRNA level in the hypothalamus [98, 99].
Much less is known about the gonadal steroid-induced changes in NA
release within the ME, although this region in rats, is particularly sensitive to ovarian hormones. However, it seems that the estrogen-dependent
increase of NA release in ME is likely to alter both GnRH release and
biosynthesis. It is suggested that NA stimulates GnRH secretion within the
ME by inducing the synthesis of prostaglandin E2 and nitric oxide in male
rats [137, 138, 155]. In anestrous ewes, the activation of GABAB receptors
agonist in the mediobasal hypothalamus-ME by specific GABAB receptor
agonist, baclophen, stimulates GnRH release; its action probably occurs by
suppressing inhibitory action of NA on GnRH release [193]. The presented
results have indicated that physiological regulation of hypothalamic GnRH
release and GnRH gene expression is associated with complex interplay of
gonadal hormones within different hypothalamic neural systems.
EFFECT OF STRESS ON GNRH/LH RELEASE AND
EXPRESSION OF GNRH AND GNRHR GENES DURING
DIFFERENT PHYSIOLOGICAL STATES
It is well documented that stressors alter the activity of many neural systems in the hypothalamus which stimulate or inhibit GnRH secretion and
Ciechanowska et al
95
that the GnRH cell response are dependent upon the kind of stress, its
duration, physiological state of animals and gender. It has been shown that
immediate response of GnRH cells to acute stress depends primarily upon
central neural systems and in some circumstances may by stimulatory in
rats [159, 185], monkeys [74] and sheep [111, 190]. These animals exposed
to acute stress respond with a small and often short-lived increase in LH
secretion. Prolonged stressful stimuli additionally modulate GnRH secretion
by hormones, neurotransmitters, neuropeptides, excitatory and inhibitory
amino acids released during the time-course of stressful stimuli, and all
these compounds released from the hypothalamo-pituitary-gonadal and
hypothalamo-pituitary-adrenal axes act mainly within the hypothalamus and
anterior pituitary gland to mediate the suppressive effect on gonadotropin
secretion [159].
Indeed, an inverse relationship between prolonged or chronic stress and
normal reproductive efficiency has frequently been observed in domesticated
animals [10, 31, 32, 38]. The psycho-emotional state evoked by prolonged
intermittent footshock stimulation of cyclic ewes suppresses the preovulatory
LH surge and, consequently, causes long-lasting disturbances in the course
of the estrous cycle in some animals [152]. Premating stress has also been
linked with lowering of the ovulation rate in ewes [45] and inhibition of the
preovulatory LH surge in heifers [121, 181]. Confinement stress stimuli affect episodic secretion of LH in ovariectomized sheep [154]. Diestrous rats
exposed to footshocks display marked changes in the course of the estrous
cycle during the post-stress period [24].
Recent findings revealed that stress affects GnRH and LH secretion by
different neuroendocrine mechanisms. Direct monitoring of the pulsatile
GnRH secretion in the pituitary portal blood has shown that psychological stress in ewes reduces the amplitude of GnRH pulses; this process is
independent of the stress-induced cortisol level [203]. However, prolonged
enhanced secretion of cortisol contributes to the suppression of GnRH
pulse frequency but only in the presence of ovarian steroids [135]. Studies
on ovariectomized sheep have indicated that either psychological stress
[16, 180] or an increment of plasma cortisol level compared to that attained
during psychological stress [17, 180] acutely reduces LH pulse amplitude
96
Regulation of GnRH secretion
by two mechanisms. First mechanism involves cortisol action via type II
glucocorticoid receptor to inhibit pituitary responsiveness to GnRH, and
second by changes in the profile of hypothalamic GnRH secretion (changes
in GnRH pulse amplitude and pulse frequency).
A number of studies have indicated a sex differences in the inhibitory
effect of cortisol on pulsatile LH secretion in sheep with rams being more
sensitive than ewes [180], and that E2 increases sensitivity to the inhibitory
actions of cortisol on LH secretion and GnRH/LH pulse frequency [135, 136].
However, in the hypothalamo-pituitary disconnected sheep model, cortisol
did not reduce the amplitude of LH pulses driven by exogenous GnRH [180];
the mechanism of this action is unknown. It may suggest that cortisol acts
indirectly via the hypothalamus to elicit a mediator that inhibits its response
to GnRH and/or that the undisturbed communication with the hypothalamus
is required to maintain cells in the anterior pituitary responsive to cortisol.
The above findings help to explain why responses to stress differ between
female and male as well as in various physiological states of females. It is
worth noting that different kinds of stress may exert a specific effect on
hypothalamic-pituitary-ovarian activity. For example, endogenous CRH
participates in the suppression of the hypothalamic-pituitary-ovarian axis
activity during some challenges, such as footshocks [160], fasting [114] and
lactation [204] but not in others, such as immune activation [15, 157].
These observations suggest that different stressors may act differently
on the hypothalamic stimulatory and/or inhibitory systems involved in the
control of GnRH cell activities; the final effect of stress on GnRH release
is determined by the net results of these systems. It was reported that different stressors may act in various manners on the activities of particular
neural systems in the brain [140]. In this respect, the stressors are divided
into four main categories: 1/ physical stressors, that have either a negative
or a positive psychological components; 2/ psychological stressors, that
reflect a learned response to previously experienced adverse conditions; 3/
social stressors reflecting disturbed interactions among individuals and 4/
stressors that change metabolic homeostasis.
Despite a number of studies on GnRH release in animals under stress
condition, there is no coherent evidence how stress affects the interneural
Ciechanowska et al
97
events related with biosynthesis of GnRH and GnRHR in the hypothalamicpituitary axis. The few results on laboratory animals have indicated that the
expression of GnRH and GnRHR genes, similarly as the gonadotropin secretion, is highly dependent upon the kind of stress, its duration, physiological
states of animals and gender. For example, cold stress suppresses GnRH gene
expression in the POA in rats [185], while prolonged food deprivation stress
does not affect GnRH gene transcription in the hypothalamus of cycling
female rats [129] but provokes a deep inhibition of GnRHR mRNA in the
anterior pituitary gland (AP). In contrast, in male rats a decreased number
of neurons expressing GnRH mRNA in the hypothalamus were found after
prolonged fasting stress [65]. Acute neurogenic stress caused similar downregulation of GnRHR gene expression in the anterior pituitary gland throughout the entire estrous cycle, but attenuated the GnRHR mRNA level in the
hypothalamus in a relatively short period at proestrus [129]. In the castrated
male rats, centrally administered IL-1β decreased GnRHR mRNA level in
the hypothalamus and LH secretion [90]. Thus, differences in the GnRH
and GnRHR gene expression in animals under various stressors during the
different reproductive states may activate or inhibit different afferents to
GnRH and GnRHR expressing neurons in the hypothalamus.
In anestrous ewes, short as well as prolonged footshock stimulation
significantly increase GnRH mRNA and GnRHR mRNA levels in the
hypothalamic-pituitary axis, but the increase of LH secretion in these
animals was noted only during acute stress [111]. These results indicate
that the neuroendocrine processes involved in the expression of GnRH and
GnRHR genes under short or prolonged stressful stimuli are distinct from
those regulating GnRH/LH secretion (tab. 1).
In the follicular phase ewes, the GnRH gene expression increased after
short footshock stimulation, whereas prolonged stressful stimuli evidently
decreased GnRH mRNA level in the hypothalamus [25]. In short-stressed
ewes, the significant increase in mRNA encoding GnRHR was detectable in
the hypothalamic-pituitary axis. However, the GnRHR mRNA levels were
reduced in the hypothalamus/stalk median eminence (SME) and AP but
were elevated in the POA of these animals. The changes in GnRH mRNA
and GnRHR mRNA in the hypothalamic-AP of the follicular phase ewes
Regulation of GnRH secretion
98
Table 1. Effects of short and prolonged footshocks stimulation* on GnRH and
GnRHR mRNA levels in the hypothalamic-anterior pituitary unit as well as LH
concentration in blood plasma of anestrous (A) and follicular phase (B) ewes
Prolonged footshocks
Short footshocks stimulation
stimulation
mRNA
GnRH
GnRHR
GnRH
GnRHR
Area
POA
AH
VM
SME
AP
LH
A
B
A
B
A
B
A
B
↑
↑
↑
nd
nd
↑
↑
↑
nd
nd
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
nd
nd
↓
↓
↓
nd
nd
↑
↑
↑
↑
↑
↑
↓
↓
↓
↓
A
↑
B
↑
A
--
B
↓
*stress was induced by repetitive trains of 3 mA alternative current of 0.5 s on and 1 s off during
20 min period of every hour; short footshocks stimulation: 3 h daily during one day (08:00 – 11:00 am);
prolonged footshocks stimulation: 5 h daily over four days (08:00 am – 01:00 pm); GnRHR: GnRH
receptor; POA: preoptic area; AH: anterior hypothalamus; VM: ventromedial hypothalamus; SME:
stalk/median eminence; AP: pituitary gland. Non stressed animals served as a control.↑: increased
level, ↓: decreased level, –: no changes, nd: not detected.
under short and/or prolonged stressful stimuli were related in a parallel way
with LH secretion (tab. 1) suggesting the existence of a direct relationship
between GnRH mRNA and GnRHR mRNA expression with GnRH and
GnRHR protein biosynthesis and GnRH release. The significance of GnRHR
mRNA in the biosynthesis of GnRH and its release in the hypothalamus of
anestrous and follicular phase ewes needs further studies.
Similarly, the differences in the expression of GnRHR gene in the POA
compared with those in the hypothalamus/SME cannot be explained adequately in follicular phase ewes subjected to prolonged stress. It is likely that
the GnRHR in the discrete hypothalamic structures are located in different
neural systems, which react in a specific way to stressful stimuli. The differences in the expression of GnRH and GnRHR genes in the hypothalamicpituitary axis in anestrous and follicular phase ewes subjected to prolonged
Ciechanowska et al
99
stress may result, as in the case of GnRH release, from the different action
of some neural systems in the hypothalamus on activities of GnRH and
GnRHR gene-expressing cells during breeding and non-breeding season.
INFLUENCE OF GABA-ERGIC SYSTEM IN THE
HYPOTHALAMUS ON THE GNRH/LH RELEASE AS WELL
AS GNRH AND GNRHR GENES EXPRESSION IN THE
HYPOTHALAMIC-ANTERIOR PITUITARY UNIT IN
FOLLICULAR PHASE EWES
The noradrenergic system in the hypothalamus of ewes has been shown to
activate GnRH/LH release from the mediobasal hypothalamus just prior to
the preovulatory LH surge [44], while in the anestrous ewes it has a rather
inhibitory influence on gonadotropin secretion [62, 193]. Consistent results
from several laboratories have shown that GABA-ergic, opioidergic and
dopaminergic systems also exert a different effect on GnRH release in ewes
during breeding and non-breeding seasons.
A large body of evidence indicates that GABA-ergic neurons in the
hypothalamus are involved in controlling GnRH release [162]. GABA, the
dominant inhibitory neurotransmitter in the hypothalamus, affects GnRH
release by two different classes of membrane receptors: GABAA [153, 175]
and GABAB [95, 127]. GABA-ergic synapses has been identified on GnRH
neurons [82, 106, 178], and GnRH cells express both types of receptors
[85, 124, 141, 145]. It has been documented that GABA acting through
a GABAA- and GABAB – receptor mechanism may stimulate [53, 78, 79, 80,
83, 122] or inhibit [4, 72, 120, 169, 170, 194, 195] GnRH release and GnRH
cell activities dependent upon the physiological state of animals, site of its
action and experimental conditions.
GABA-ergic neurons may also serve as a primary integrating center for
many different inputs to GnRH. Signals from steroid hormones [43, 184]
and neural systems in the hypothalamus [43, 183] have been shown to alter
the GABA-ergic drive to GnRH neurons which may contribute to a change
in GnRH output.
100
Regulation of GnRH secretion
It is generally accepted, that muscimol, a selective agonist of GABAA
receptor, decreases LH secretion in sheep [169, 170, 194, 195]. The effects of
bicuculline (GABAA receptor blocker) on this hormone secretion, however,
have been variable. In ovariectomized ewes, injection of bicuculline into
the POA inhibited LH secretion under all conditions except the breeding
season when LH secretion was greatly suppressed by estrogens [169, 170].
Perfusion of bicuculline into the POA or ventromedial hypothalamus (VM)
of follicular-phase ewes had no evident effect on extracellular concentrations
of GnRH in the perfusates [194, 195]. Dialysis of this drug into the POA of
castrated rams reduced LH release [55]. Thus, in sheep the effect of a blockade
of GABAA receptor on GnRH/LH release is highly dependent upon physiological states and gender. It has been documented in in vitro studies that the
activation of GABAA receptors depolarizes as well as hyperpolarizes GnRH
cells [39, 67] and that the endogenous GABA can excite and inhibit the firing
of GnRH neurons [68, 122]. Studies exploring the effects of GABAA receptor
antagonists on GnRH neurons showed that the majority of these cells were
depolarized and/or excited by blocking of GABAA receptors [68].
The mechanism underlying the effect(s) of GABA on the release of
GnRH and GnRH cell activity is still poorly understood. Perhaps the most
reasonable explanation for contradictory data may be the assumption that
GABAA receptors are located not only on GnRH neurons but also on numerous stimulatory and inhibitory interneurons that impinge on GnRH cells;
the final effect of their action is determined by the net results of inhibition
and disinhibition of these systems controlling the GnRH neurons activity.
It is also documented that in rodents, GABA acts via GABAB receptors
to reduce GnRH secretory activity. Pharmacological activation of these
receptors by agonists inhibits the preovulatory LH surge [3, 4, 5] as well
as the neurotransmitter-mediated stimulation of GnRH/LH release [6, 72,
116]. In addition, GABAB receptor systems are involved in mediating the
suppressive actions of GABA on pulsatile LH release [5]. In contrast, in
ovariectomized-estrogen treated ewes [170] and castrated testosteroneprimed rams [54, 80] during non-breeding season, the activation of GABAB
receptors in the POA or VM by baclofen (a GABAB receptor agonist) greatly
increases GnRH/LH secretion. On the other hand, neither activation nor
Ciechanowska et al
101
the blockade of GABAB receptors in ovariectomized estrogen-treated ewes
during the breeding season affects GnRH/LH secretion [169, 170].
Available data have shown that changes in GABA-ergic neurotransmission
in the hypothalamus of rats also affect the expression of GnRH [56, 89, 105]
and GnRHR [165, 173] genes. The modulation of the activities of GABAA and
GABAB receptors strongly suggests that each receptor acts on GnRH gene
expression in a specific way and that the influence of GABAA receptors on
GnRH gene expression mostly depends upon the experimental condition. It
has been shown that chronic stimulation of GABAA receptor decreases GnRH
transcript [56, 107] whereas acute treatment with low, but not high, doses of
muscimol increases GnRH mRNA levels in the POA/anterior hypothalamus
(AH) area in rats [89]. Stimulation of GABAB receptors with baclofen augments hypothalamic GnRH mRNA level in a dose-dependent manner [89].
In follicular phase ewes, the prolonged modulation of GABAA receptor activities in the hypothalamus profoundly affects the expression of GnRH and GnRHR
genes in the hypothalamic-pituitary axis (tab. 2). The activation of GABAA receptors caused a significant reduction in GnRH and GnRHR transcripts, whereas
inhibition of GABAA receptor activity increased GnRH mRNA and GnRHR
mRNA levels suggesting that down- or up- regulation of GnRH and GnRHR
gene expression is dependent upon central GABA-ergic action [26]. The decrease
or increase in hypothalamic GnRH mRNA and GnRHR mRNA levels of ewes
were parallel to GnRHR gene expression in the anterior pituitary gland and LH
secretion. They indicate that GABA acting through the GABAA receptor mechanism on GnRH and GnRHR genes expression in the hypothalamus is involved
in biosynthesis of GnRH and GnRHR protein and release of GnRH.
THE CENTRAL EFFECT OF Β-ENDORPHINERGIC SYSTEM
ON THE GNRH/LH RELEASE AS WELL AS GNRH AND GNRHR
GENES EXPRESSION IN THE HYPOTHALAMIC-ANTERIOR
PITUITARY UNIT IN FOLLICULAR PHASE EWES
Evidence for the role of opioidergic peptides in the hypothalamus within
the GnRH network has shown that β-endorphin constitutes important
*the infusions of Ringer’s solution into the third cerebral ventricle of control ewes were performed at a rate of 2 μl/min during 20 min of every hour
for five hours daily (08:00 am – 01:00 pm) on 14th – 16th days of the estrous cycle. The drug-treated ewes received infusion of β-endorphin, naloxone
(antagonist of μ-opioid receptors), muscimol (agonist of GABAA receptors), bicuculline (antagonist of GABAA receptors) CRH or α-helical CRH9-41
(CRH-antagonist; 20 µg of respective drug/ml Ringer’s solution). GnRHR: GnRH receptor; POA: preoptic area: AH: anterior hypothalamus; VM:
ventromedial hypothalamus; SME: stalk/median eminence; AP: pituitary gland. In comparison to control ewes: ↑: increased level, ↓: decreased level,
–: no changes, nd: not detected.
POA
AH
VM
SME
AP
LH
B
C
β-endorphin
nalokson
muscimol
biccuculine
CRH
CRH-antagonist
GnRH GnRHR GnRH GnRHR GnRH GnRHR GnRH GnRHR GnRH GnRHR GnRH GnRHR
↓
↑
--↓
↓
↑
↑
↓
↑
↑
↓
↓
↓
--↓
↓
↑
↑
↓
↓
↑
-↓
↓
--↓
↓
↑
↑
↓
↓
↑
↑
↓
-↓
↑
↓
↑
nd
nd
nd
nd
nd
nd
↓
-↓
↑
↓
↑
nd
nd
nd
nd
nd
nd
↓
-↓
↑
↓
↑
A
Table 2. Effect of stimulation or inhibition of µ-opioidergic (A), GABAA-ergic (B), and CRH-ergic (C) receptors on GnRH
and GnRHR mRNA levels in the hypothalamic-anterior pituitary unit and LH concentration in blood plasma of follicular
phase ewes*
102
Regulation of GnRH secretion
Ciechanowska et al
103
inhibitory compound of the neural circuitry in the hypothalamus that involved in the central control of GnRH secretion in ewes and other species
during the estrous cycle [33, 36, 44, 52, 76, 77, 197]. Cell bodies containing β-endorphin are exclusively located in the periarcuate region of the
hypothalamus [177, 179, 206]. β-endorphin nerve terminals synapse on
perikarya and dendrites of GnRH neurons [82, 189] and can affect GnRH
release at two levels: POA and VM /SME. The GnRH fibers in the hypothalamus also contain opioid receptors [48, 75, 179] and β-endorphinergic
neurons are connected indirectly with GnRH cells through GABA-ergic
[52], nitricoxidergic [52], noradrenergic [43, 75, 91, 92], dopaminergic [192,
197] and NPY-ergic cells [43] raising the possibility that β-endorphinergic
sensitive interneurons may also indirectly modulate GnRH release and
GnRHR gene expression.
It was found that β-endorphin has a suppressive effect on GnRH/LH
release in ewes during the estrous cycle but not in seasonally anestrous animals [29, 197]. Recent studies have shown that infusion of β-endorphin into
the third cerebral ventricle of follicular phase ewes decreases GnRH gene
expression in the hypothalamus and leads to complex changes in GnRHR
mRNA level in discrete hypothalamic areas (tab. 2): an increase in the POA,
no changes in the AH and a decrease in VM/SME [29]. In β-endorphintreated ewes, the GnRHR mRNA level in the anterior pituitary gland and
LH secretion decreased significantly. This suggests that β-endorphin may
participate in the processes of biosynthesis of GnRH and GnRHR.
However, the physiological importance of GnRHR mRNA in different
parts of the hypothalamus in the control of GnRH secretion waits to be established. The inverse relationship between the preoptic area GnRHR mRNA
and GnRH mRNA in the β-endorphin-treated ewes raises the possibility
that GnRHR gene-expressing neurons in this structure may be involved in
the control of GnRH cell activities. This suggests that the increase of GnRHR neurons in the POA may down-regulate GnRH gene expression. On
the other hand, the decrease of GnRHR mRNA in the VM/SME in these
animals may be due to an increase in the utilization of GnRHR mRNA
in posttranscriptional processes in the biosynthesis of GnRHR. Increased
activity of GnRHR in the VM may suppress GnRH release. It is generally
104
Regulation of GnRH secretion
believed that the activation of GnRHR in the VM can exert an inhibitory
[40, 167] effect on GnRH release in rats and an increase in GnRHR mRNA
level in this structure [84, 124].
EFFECT OF MODULATION OF THE CRH-ERGIC ACTIVITY
ON THE GNRH/LH SECRETION AND EXPRESSION OF GNRH
AND GNRHR GENES IN THE HYPOTHALAMIC-ANTERIOR
PITUITARY UNIT IN FOLLICULAR PHASE EWES
CRH is one of numerous neurotransmitters/neurohormones in the central
nervous system that interact together in various structures of the brain to alter
the activity of GnRH neurons during certain challenges. Most in vivo and
in vitro studies have shown that CRH can act directly on GnRH perikarya
via synaptic contacts in the POA as well as on GnRH nerve terminals in
the SME to suppress GnRH release [58, 75, 113, 130]. Evidence of CRH
interferences with GnRH neural activity was also confirmed in experiments performed on rats in which CRH antagonist reversed or attenuated
the inhibitory influence of CRH on GnRH/LH secretion [114, 158, 160].
However, the pathways and mode of action of CRH on GnRH cells is still
not well recognized. CRH action on GnRH neurons may represent a local
connection between CRH and GnRH cells in the POA as well as neural CRH
projection from other hypothalamic and extrahypothalamic areas to GnRH
neurons [43, 119, 158, 159]. A number of immunohistochemical and physiological studies have also shown that the mechanism through which CRH
affects GnRH release involves the modulation of other pathways including
catecholaminergic, serotoninergic, GABA-ergic, opioidergic systems.
The concept that catecholaminergic systems are involved in CRHinduced suppression of GnRH/LH secretion is based on observations that
systemic- or intracerebroventricularly (icv)-injected CRH inhibits GnRH/
LH secretion [158] and facilitates NA release in rats [47, 49] and NA output
in sheep [151, 191]. CRH administered intraventricularly or directly into the
locus coeruleus in rats increases the release of NA in areas receiving projections from this structure [43]. CRH containing axon terminals synapse onto
Ciechanowska et al
105
catecholamine dendrites and may presynaptically modulate other afferents
in the rostral pole of locus coeruleus in the rat brain [202]. With respect
to serotonin, it has been presented that the administration of CRH inhibits
5-HT release and raphe neural activity [149]. In rats, the serotoninergic
axon terminals from raphe nuclei project into the POA to enhance GnRH
secretion [179]. Similarly, it has been documented that CRH synapse on
GABA cells rising the opportunity to react indirectly with GnRH neurons
[34, 43]. CRH stimulates GABA-ergic system; an infusion of CRH into
the locus coeruleus resulted in a significant increase in the percentage of
immunoreactive GAD67 (isoform of glutamic acid decarboxylase) within
the POA [119].
Additionally, CRH cooperates with the opioidergic system in the hypothalamus in the control of GnRH release [131, 132, 133]; its effect is
dependent upon sex steroids [19, 20] and may be species-specific [158].
It has been shown that CRH inhibits LH secretion in gonadectomized
monkeys and rats through a mechanism that depends partially on opioid
tone [8, 59, 139, 147]. However, a similar stimulation during follicular and
luteal phases is totally ineffective in monkeys [134]. On the other hand,
long-term gonadectomized rats do not respond along with the suppression
of LH secretion to opioid [7] or CRH treatment [132]. In ovariectomized
or intact sheep, peripheral or central administration of CRH during
anestrus or breeding season has generally no effect on GnRH release [31,
46, 142]. However, during the preovulatory period the icv infused CRH
does not affect tonic LH secretion but suppresses the preovulatory LH
surge and prolongs the estrous cycle [148]. In contrast, GnRH/LH secretion is stimulated by CRH during non-breeding and breeding seasons in
ovariectomized progesterone-estradiol-treated ewes in which LH pulse
frequency is low [19].
The experiments on the immortalized neural cell line (Gn11) evidenced
that CRH-like peptides affect GnRH gene expression acting through CRH
receptors on these cells [186, 187]. The infusion of CRH or CRH antagonist (α
helical CRH 9-41) into the third cerebral ventricle of ewes caused a decrease
or increase in GnRH gene expression in the hypothalamus, respectively, and
led to different responses in GnRHR gene expression in the discrete parts
106
Regulation of GnRH secretion
of the hypothalamus [30]. CRH increased GnRHR mRNA in the POA and
decreased it in the AH and VM, and SME (tab. 2). In CRH-treated animals
GnRHR mRNA decreased significantly in the anterior pituitary gland and
LH in blood. The blockade of CRH receptors exerted opposite effects on
GnRHR gene expression to that induced by CRH. Presented results suggest
that CRH acting through CRF-receptor mechanism(s) in the hypothalamus
may decrease GnRH biosynthesis and its release through increased GnRHR
expression in the hypothalamus.
Altogether, the decrease of GnRH mRNA level in the hypothalamus
after the stimulation of µ-opioidergic, GABAA-ergic and CRH-ergic receptors with a concomitant decrease in LH secretion suggests that the activation of these receptors has a suppressive effect on GnRH biosynthesis and
consequently on GnRH release. Such an assumption seems to be supported
by observation that the blockade of these receptors leads to an increase of
GnRHR mRNA level in the anterior pituitary gland and LH secretion. The
specific responses in GnRHR gene expression in the discrete parts of the
hypothalamus to agonists and/or antagonists of μ-opioidergic, GABAA-ergic
and CRH-ergic receptors in follicular phase ewes, suggests that the GnRHR
in various parts of the hypothalamus are located on different neural systems.
It is likely that the decrease or increase in GnRHR mRNA levels in the VM/
SME after the stimulation or inhibition of these receptors may result from
the increase or decrease, respectively, in the utilization of GnRHR mRNA
in the biosynthesis of GnRH-R in this structure. The increase of GnRHR
activity in this structure of rats has a suppressive effect on GnRH release
[40, 167].
IMPLICATION OF DOPAMINERGIC SYSTEM IN THE
HYPOTHALAMUS OF ANESTROUS EWES ON LH RELEASE
AS WELL AS GNRH- AND GNRH-R GENES EXPRESSION IN
THE HYPOTHALAMIC-ANTERIOR PITUITARY UNIT
It is generally accepted that the annual reproductive cycle in sheep and
other seasonal breeders are primarily induced by photoperiodic-mediated
Ciechanowska et al
107
changes in the activity of several neuroendocrine systems and their functions in controlling GnRH release from the hypothalamus [82, 110]. It
has been proposed that melatonin signals, which encode photoperiods,
act within the VM to affect GnRH secretion [115] through several neural
pathways including dopaminergic [2, 61, 197, 198], noradrenergic [60, 62,
193], serotoninergic [102], opioidergic [36, 197] and GABA-ergic [169, 193]
systems.
It has been established that among these transsynaptic pathways regulating GnRH cell activity, the dopaminergic systems in the hypothalamus
have a predominant inhibitory effect on GnRH release in the non-breeding
season (long-day) but not in the breeding season (short-day; [2, 13, 61, 197]).
Numerous studies support the notion that increased dopaminergic system
activity in the hypothalamus of anestrous ewes suppresses GnRH release,
whereas reduced activity of these systems during short day increases pulsatility in GnRH/LH secretion [63, 197, 198]. Pharmacological blockade
of dopaminergic systems with specific dopaminergic antagonists [35, 73,
198] as well as surgical [143, 150] or chemical [188] disruption of dopaminergic pathways between ME and POA resulted in significant increases in
GnRH/gonadotrophin secretion in sexually inactive animals during long
days. Dopaminergic receptor agonists failing to suppress LH secretion
during the non-breeding season in sheep are consistent with the views that
inhibitory dopaminergic systems are strongly activated during long-day
photoperiod [197, 198]. In contrast, the specific dopaminergic antagonists
were ineffective in simulating pulsatile LH secretion when given to breeding ewes, whereas dopaminergic agonists displayed a suppressive effect on
gonadotropins release [197, 198]. However, it is becoming obvious that there
are a number of dopaminergic pathways which influence gonadotropin by
either increasing or decreasing that secretion [9, 81, 88]. These include A12,
A13 and A15 (brain dopaminergic nuclei), dopaminergic cell groups with
each pathway apparently modulating the LH pulse generator independently
[2, 9, 88, 104, 123].
The most likely location of dopaminergic cells that inhibit GnRH
pulse frequency during anestrus is the A15 cell group [2]. Lesion studies have documented the participation of A15 dopaminergic neurons in
108
Regulation of GnRH secretion
E2-mediated feedback action on GnRH secretion during anestrus [2].
Because dopaminergic neurons do not contain estrogen receptors [103,
177], estrogen sensitive neural afferents to A15 groups cells are likely to
project from the ventromedial part of the POA [9] and retrochiasmatic
structure [57, 69]. Thus, a neural circuit consisting of estrogen sensitive
neurons in these areas which project to inhibitory A15 dopaminergic cells
afferent to GnRH neurons mediates estrogen negative action in anestrus.
The seasonal changes in morphology and the number of synapses on A15
neurons further support this concept [2]. The dopaminergic terminals
which are located in the external layer of the ME establish synaptic contact with GnRH terminals suggesting that dopamine may presynaptically
control GnRH release [101]. The morphological and functional observations revealed that the dopaminergic neurons are capable of affecting
the GnRH cells indirectly through opioid systems in the hypothalamus
[197]. It has been indicated that opiodergic systems in the hypothalamus
of anestrous ewes display a minor role in the suppression of GnRH/LH
release [77, 190, 197].
Recent studies have demonstrated that dopaminergic neurotransmission
through dopaminergic DA-2 receptor affects not only GnRH release but also
GnRH and GnRHR gene expression in the hypothalamus of anestrous ewes
[28]. Indeed, the blockade of DA-2 receptors by the antagonist, sulpiride,
significantly decreased GnRH mRNA level in the ventromedial hypothalamus; such treatment had no evident effect on GnRH gene expression in the
preoptic/anterior hypothalamic area. The infusion of sulpiride in the third
cerebral ventricle of the brain significantly increased GnRHR mRNA level
in the POA/AH areas but decreased them in the VM/SME. All these changes
in GnRH mRNA and GnRHR mRNA levels in selected parts of the hypothalamus were associated with an increase in GnRHR gene expression in
the anterior pituitary gland and LH secretion.
These results strongly suggest that the dopaminergic system acting
through DA-2 receptors in the hypothalamus is involved in the regulation
of GnRH and GnRHR gene expression in specific coordinated fashion,
which leads to changes in the biosynthesis of GnRH and its release in
anestrous ewes. It is likely that the decreased GnRH mRNA level in
Ciechanowska et al
109
the VM after the blockade of dopaminergic DA-2 receptors is related
to increased utilization of GnRH mRNA in biosynthetic processes of
GnRH. Such an assumption is supported by increased expression of
GnRHR gene in the anterior pituitary gland and LH secretion. A lack
of significant changes in the GnRH mRNA level in the POA/AH areas
of sulpiride-treated ewes suggests that the blockade of DA-2 receptors
did not evidently affect transcriptional activity of the GnRH gene. The
blockade of DA-2 receptor gene led to different responses in GnRHR
mRNA level in various parts of the hypothalamus: increased GnRHR
mRNA in the POA/AH areas and decreased GnRH mRNA content in
the VM/SME. The regional specific differences of GnRHR expressing
neurons in various parts of the hypothalamus to dopamine may be due to
their different response to the blockade of dopaminergic receptors as well
as to dopaminergic sensitive interneurons inputs. It could be presumed
that the decrease in GnRHR mRNA level in the VM/SME is associated
with a decreased biosynthesis of GnRHR protein which, in turn, allows
an increase in GnRH release.
EFFECT OF GNRH ON THE LEVELS OF GNRH mRNA AND
GNRHR mRNA IN THE HYPOTHALAMUS OF ANESTROUS
EWES
It has been shown that the hypothalamic GnRH, among other neurohormones and/or neurotransmitters, is involved in the control of GnRH release
through ultrashort loop feedback mechanism. It has been proven in vivo and
in vitro studies that the activation of GnRH receptors in the ventromedial
hypothalamus with GnRH exerts an inhibitory effect on GnRH release from
the GnRH terminals in rats [40, 167]. In the anestrous ewes, the prolonged
intermittent stimulation of GnRHR in the hypothalamus with the infusion
of GnRH into the third ventricle increases GnRH mRNA in the VM and
GnRHR mRNA in the entire hypothalamus. This suggests that GnRH at
the genomic level in the hypothalamus may act on both GnRH and GnRHR
synthesis and, consequently, alter GnRH release [112].
110
Regulation of GnRH secretion
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