Jurnal GNRH 3

Theriogenology 66 (2006) 691709
www.journals.elsevierhealth.com/periodicals/the
Review
Gonadotropin-releasing hormone (GnRH) and its natural

analogues: A review
Falk Schneider a,*, Wolfgang Tomek a, Carsten Grundker b
a
Department of Reproductive Biology, Research Institute for the Biology of Farm Animals, Wilhelm-Stahl-Allee 2,
D-18196 Dummerstorf, Germany
b
Department of Gynecology and Obstetrics, Georg-August-University, Gottingen, Germany
Received 28 July 2005; received in revised form 20 January 2006; accepted 17 March 2006
Abstract
The pivotal role of gonadotropin-releasing hormone (GnRH) during the hormonal regulation of reproductive processes is
indisputable. Likewise, many factors are known to affect reproductive function by influencing either GnRH release from
hypothalamus or pituitary gland responsiveness to GnRH. In veterinary medicine, GnRH and its agonists (GnRHa) are widely
used to overcome reduced fertility by ovarian dysfunction, to induce ovulation, and to improve conception rate. GnRHa are,
moreover, integrative part of other pro-fertility treatments, e.g. for synchronization of the estrous cycle or stimulation for embryo
transfer. Additionally, continuous GnRH which shows desensitizing effects of the pituitary-ovarian axis has been recommended for
implementation in anti-fertility treatments like inhibition of ovulation or reversible blockade of the estrous cycle. Just as much,
another group of GnRH analogues, antagonists, are now in principle disposable for use.
For a few decades, GnRH was thought to be a unique structure with a primary role in regulation gonadotropins. However, it
became apparent that other homologous ligands of the GnRH receptor (GnRHR) exist. In the meantime, more than 20 natural
variants of the mammalian GnRH have been identified in different species which may compete for binding and/or have their own
receptors. These GnRH forms (GnRHs) have apparently common and divergent functions. More studies on GnRHs should
contribute to a better understanding of reproductive processes in mammals and interactions between reproduction and other
physiological functions. Increased information on GnRHs might raise expectations in the application of these peptides in veterinary
practice. It is the aim of this review to discuss latest results from evolutionarily based studies as well as first experimental tests and to
answer the question how realistic might be the efforts to develop effective and animal friendly practical applications for endogenous
GnRHs and synthetic analogues.
# 2006 Elsevier Inc. All rights reserved.
Keywords: Reproduction; Farm animals; GnRH; Hypothalamus; Gonadotropin
Contents
1.
2.
3.
4.
Introduction to gonadotropin-releasing hormone . . . . . . . . . .

Biosynthesis and storage of GnRH-I and its natural analogues
Release mechanisms of GnRH-I . . . . . . . . . . . . . . . . . . . . .
Reception of GnRH-I and its variants. . . . . . . . . . . . . . . . . .
* Corresponding author. Tel.: +49 38208 68757; fax: +49 38208 68752.
E-mail address: falk.schneider@fbn-dummerstorf.de (F. Schneider).
0093-691X/$ see front matter # 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.theriogenology.2006.03.025
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
692
692
694
696
692
5.
6.
F. Schneider et al. / Theriogenology 66 (2006) 691709
Hypophyseal and extrahypophyseal effects of natural GnRHs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Use of GnRH-I and its natural forms in farm animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction to gonadotropin-releasing
hormone
GnRH belongs to a group of neuropeptides originally
discovered and successfully isolated as factors of
hypothalamic origin that control secretions of the
anterior pituitary gland. GnRH influences reproductive
processes, mainly by regulating pituitary gonadotropin
synthesis and release, which in turn modulate steroidogenesis and gametogenesis. This pivotal role may
explain why the interest in GnRH is still going on since
its primary structure was revealed in pigs [1] and sheep
[2]. GnRH is expressed, apart from hypothalamus, in
numerous peripheral tissues including gonads and
placenta [310]. Hypothalamic and extrahypothalamic
GnRH are known as integrated part of multiple
paracrine/autocrine axes. Hypothalamic GnRH, however, is in the focus of attention of the present review.
There are currently 23 identified naturally occurring
GnRH analogues (GnRHs) across the vertebrate species
[1113]. These variants show multiple substitutions in
their amino acid (AA) sequence when compared with the
mammalian GnRH (mGnRH), and they were widely
distributed in tissues suggesting that they have acquired
significant functions through the phylogeny. GnRHs have
been explored during last years in various classes of
vertebrates, mainly in fishes and mammals, but also in
protochordates, that are phylogenetically distant from
mammalian vertebrates. The species-related designation
of single GnRH isoforms may be difficult to survey and
confusing under circumstances. In this review mGnRH
will always be designated, according to [14], GnRH-I,
chicken GnRH-II (cGnRH-II) GnRH-II, and salmon
GnRH (sGnRH) GnRH-III. Other GnRHs will be
preferably discussed by citing the traditional names
which have been introduced in the literature. It was
assumed that dogfish GnRH, GnRH-II, and GnRH-III are
ancient forms which could be likely found in invertebrates [15]. At this stage, the exploration of the primary
structure of GnRHs has been completed only in tunicates
and octopus. More information seems to be necessary to
complete the phylogenetic tree of GnRH and to
characterize the ontogenic development of single GnRHs
in different species [16].
GnRH-I and its variants are thought to have
neuroendocrine, as well as neurotransmitter and neuro-
698
700
703
modulatory functions [13,17]. The neuroendocrine axis

plays the central role in the control of reproduction, and
GnRH-I is well known to integrate internal and external
signals of the nervous system to reproductive system
[15]. In invertebrates, a similar role of GnRHs may have
evolved resulting in systems that assure the maintenance
of species under changing environments. However,
GnRH-I also acts as a neuromodulator probably by
down-regulation of its neighboring genes for particular
protein-tyrosin phosphatases [18]. This GnRH-I function
could be an important link of the common molecular
mechanism underlying the diverse functions of GnRHs.
It is evident that at least two of these natural GnRHs
are present in more than 80 vertebrate species [12
14,1921]. A better understanding is, however, still
needed to evaluate the specific contribution of GnRHs
to the control of mammalian reproduction by GnRH-I in
mammals. The practical usefulness of GnRH-I and its
synthetic analogues (agonists and antagonists) has
achieved a high level. It is the purpose of the present
review to discuss in this context the prospects for
GnRH-II and other GnRHs although the exact functions
of these peptides are yet to be defined [22].
2. Biosynthesis and storage of GnRH-I and its
natural analogues
Like many other proteins and peptides, GnRH-I and
its analogues are enzymatically processed from larger
precursors (Fig. 1). The complementary DNA consists
of the decapeptide, extended at the amino (N) terminus
by a signal peptide, and at the carboxy (C) terminus by a
Gly-Lys-Arg sequence followed by the GnRH-associated peptide (GAP).
In the proGnRH-I, the GAP sequence is 56 AA long
but it shows, like the signal peptide, considerable
variations between several mammals [3] like that of
pro-GnRHs of other species [23,24]. GAP which is
Fig. 1. Schematic representation of the prepro-GnRH precursor proteins. The 50 -untranslated region (50 utr) is followed by the signal
peptide (SP), the GnRH, processing signal (*), the GnRH-associated
peptide (GAP), and the 30 -untranslated region (30 utr). Adapted to
Sherwood et al. [3].
consequently co-secreted with GnRH [10,25] may be

involved in the correct processing and packing of the
decapeptide [3]. The processing of GnRH-I occurs
within about 1000 GnRH neurons that do not reside in
defined cytoarchitectonic bound-areas among different
species [26]. GnRH neurons are distributed in a loose
array along the ventral medial forebrain from the
posterior olfactory bulbs to the arcuate nucleus. GnRH
neurons are found in the vicinity of the olfactory
placode during prenatal development, and then the
GnRH-producing cells migrate through the nasal
system into the forebrain [27]. Therefore, differences
in GnRH-producing areas within the brain appear to
result from greater or lesser penetration along the
olfactory-forebrain-hypothalamus continuum to the
median eminence. The unusual developmental course
of GnRH neurons may represent a vestige of the
pheromonal control of reproductive function and, thus,
explain the release and transportation of GnRH into the
hypothalamus-pituitary portal vasculature and the
clinical link between reproductive failure and olfactory
dysfunction, respectively [28].
693
Apart from GnRH-I and, very often, GnRH-II

[17,2931] the presence of a third form, lamprey
GnRH-III (lGnRH-III), has been determined in neurons
of the preoptic-hypothalamic region of the rat, both
alone and together with GnRH-I [32]. Others were,
however, not able to isolate lGnRH-III in humans [8,30]
or in hamster and rat brains [29]. The primary AA
structure of most GnRH peptides is common: a length of
10 AA and conserved AA in positions 1 to 4, 9, and 10
(Table 1). The compositions of the peptide chains of
natural GnRHs show a range of substituted AA from
one (e.g. cGnRH-I) to five (lGnRH-I) compared with
GnRH-I. The AA sequence of GnRH-II shows, for
example, differences in positions 5 (His for Tyr), 7 (Trp
for Leu), and 8 (Tyr for Arg), compared with that of
GnRH-I. There are, however, some striking exceptions
of common composition, e.g. the sequences of guinea
pig (gp)GnRH, lGnRH-I, and octopus (o)GnRH [15,17]
(Table 1).
The listing of GnRHs demonstrates that the main
part of them was found in evolutionarily old life forms
and fewer variants occur in mammals, respectively [33].
Table 1
Amino acid composition of GnRH-I and its 23 natural analogues in vertebrates and invertebrates
Amino acid
1
10
Vertebrate
Mammal (GnRH-I)
Guinea Pig
Chicken-I
Rana
Seabream
Salmon (GnRH-II)
Whitefish
Medaka
Catfish
Herring
Chicken-II (GnRH-II)
Dogfish
Lamprey-III
Lamprey-I
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
His
Tyr
His
His
His
His
His
His
His
His
His
His
His
His
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Tyr
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Phe
His
His
His
His
His
Leu
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Asp
Glu
Leu
Val
Leu
Leu
Leu
Trp
Met
Leu
Leu
Leu
Trp
Trp
Trp
Trp
Arg
Arg
Gln
Trp
Ser
Leu
Asn
Ser
Asn
Ser
Tyr
Leu
Lys
Lys
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Invertebrate
Octopus
Tunicate-I
Tunicate-II
Tunicate-III
Tunicate-IV
Tunicate-V
Tunicate-VI
Tunicate-VII
Tunicate-VIII
Tunicate-IX
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
His
His
His
His
His
His
His
His
His
His
Phe
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Asn
Asp
Leu
Tyr
Asn
Tyr
Lys
Tyr
Leu
Asn
Gly
Tyr
Cys
Glu
Gln
Glu
Gly
Ala
Ala
Lys
Trp
Phe
His
Phe
Leu
Tyr
Tyr
Leu
Leu
Leu
His
Lys
Ala
Met
Thr
Met
Ser
Ser
Ser
Ala
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
Asn
Tyr
Bold letters: primary structure of GnRH-I and identical amino acids in variants. Adapted to Gorbman and Sower [15] and Millar et al. [17].
694
The most ancient GnRH form is thought to be oGnRH

[34]. Another form of GnRH, 9-hydroxyproline GnRHI (Hyp9-GnRH), has been reported to be present in
various mammals like rats and dogs. The peptide has a
nearly identical structure to GnRH-I but the small
difference in the 9th AA makes it less sensitive to prolyl
endopeptidase [3537]. The answer to the question
whether various GnRH forms [38] and their genes
[21,3943], respectively, are present in a distinct
species may have some importance for the understanding of the evolution and be helpful to draw up
specific functions of GnRHs in mammals. The
phylogenetic tree which was recently established [15]
contains the AA structures of the natural GnRHs
(Fig. 2).
The GnRH-II structure ([His5,Trp7,Tyr8]-GnRH;
Table 1) has been conserved over 500 million years
[12,21]. GnRH-II is one of the GnRHs that appears to be
predominantly expressed in other tissues such as the
reproductive system [22]. In the brain of mammals, the
vast majority of GnRH-II cell bodies are localized to the
midbrain, with a few present in hypothalamic and
extrahypothalamic regions [44] and a minority of fiber
projections from neurons containing GnRH-II project to
the median eminence or regions that regulate gonadotropin release [45]. In the human, however, GnRH-II is
expressed at significantly higher levels outside the
brain, e.g. in the kidney, bone marrow, and prostate [40].
Other species-specific prerequisites of the biosynthesis
of GnRHs were reported for lGnRH-III [46] and GnRHIII [47] in several mammals.
3. Release mechanisms of GnRH-I

The release of hypothalamic GnRH-I is not
continuous but pulsatile. The episodic release of GnRH
during the female reproductive cycle is seen as a
prerequisite for fertility. Multiple rhythms interact to
generate GnRH-I pulses, thus high-frequency burst
rhythms decrease during peaks in the low-frequency
rhythm with approximately 20 min duration. The
pulsatile release pattern is the predominant one in
most physiological circumstances. The sole exception
to pulsatility is at the time of the preovulatory LH.
Several theses were postulated to understand the
mechanisms underlying episodic GnRH-I release.
One of the theses is that interactions among GnRH
neurons should be crucial for synchronizing and
modulating the low-frequency rhythm which is associated with hormone release [48].
Numerous loops, ultra-short, short and long in
length, form a link between the hormone-secreting
tissues. Paracrine interactions among GnRH neurons
are known, for example, as the first proposed ultra-short
loop [49]. The real frequency of GnRH pulses in an
individual is species-specific and depends on its gonadal
hormone status and numerous other factors [50,51]. The
role of the ovarian steroids estradiol (E2) and
progesterone (P4) in the control pulsatile GnRH
secretion and generation of the preovulatory GnRH
surge to induce the release of the LH surge seems to be
well investigated [23,52]. Both steroids interfere with
gonadotropin regulation by modifying the secretion of
Fig. 2. Phylogenetic analysis of 24 GnRH primary amino acid structures (bold letters: GnRHs with demonstrated or supposed importance to
mammalian reproduction). Adapted to Gorbman and Sower [15].
GnRH or exhibit a direct effect on gonadotropinsecreting cells in the anterior pituitary gland. There is
some evidence to suggest that the negative feedback
actions of E2 are manifest in the suppression of GnRH
pulse amplitude and P4 may primarily exert its effects
on GnRH pulse frequency. In the mid-luteal phase of the
estrous cycle, for example, the negative feedback of P4
suppressed GnRH release as well as decreased the
expression of the GnRH mRNA in heifers [53]. In
sheep, the negative feedback of E2 on the episodic
GnRH secretion was found to be highly effective during
anestrus [54]. The understanding of the effects of
gonadal steroids on synthesis of GnRH-I is less clear
than that on secretion [23]. Apart from direct effects
other effects are transmitted through steroid-responsive
neuronal systems in various parts of the brain. They can
override direct effects under special situations, e.g.
undernutrition and stress.
High levels of estrogens produced during the
preovulatory period exert a positive feedback action,
probably by culminating in the release of increased
GnRH amounts and gonadotropin surges. Previously, it
was assumed that E2 stimulates the expression of the
gene encoding the GnRH receptor. The increase
precedes the preovulatory rise in circulating concentrations of E2. The enhanced pituitary sensitivity to
GnRH may occur as a result of a decrease in
concentrations of P4 rather than in an increase in E2
concentrations [55].
Moreover, there have been reported effects of
various hormones of non-reproductive organs and
tissues, e.g. cortisol from adrenals or leptin from fat
cells, which may act on the hypothalamus to influence
pulsatile GnRH release and/or on the pituitary gland to
inhibit gonadotropin responsiveness to GnRH [5662].
The secretion of GnRH during the reproductive cycle is,
furthermore, the result of qualitative and quantitative
modifications in neurotransmitter systems, e.g. catecholaminergic, opioidergic and GABAergic systems,
which show great differences in their impact [8,23,63
70]. It was summarized [71] that many compounds can
potentially modify the GnRH-I-induced secretion of
gonadotropins by different ways:
Peptides, e.g. oxytocin, are transported from the
hypothalamus and directly acts on the gonadotrope.
There is an interaction of the peptides, e.g. neuropeptide Y, from the hypothalamus with GnRH-I.
Peptide elicits release of another substance that acts
on the gonadotrope and so produces a paracrine
mechanism of action, e.g. PACAP stimulates IL-6
release from folliculo-stellate cells.
695
Peptide is released from a cell within the pituitary, e.g.

galanin from lactotropes.
An autocrine process utilizing peptide synthesized
within the gonadotrope, e.g. substance P.
The gonadotropins LH and FSH are dimeric
glycoprotein hormones, showing a common a-subunit
while possessing distinct b-subunits, the latter conferring biological actions [72]. The subunits are
encoded by different genes, and the expression may
be regulated in either a coordinate or differential fashion
[73]. Gonadal steroid and peptide hormones can exert
selective actions on one or more of the subunit gene
products [52,74]. It is a striking feature that GnRH
induces potentiation of its own action on the LH
response by the phenomenon self-priming which
means a biphasic LH response. Recently, it was argued
that ovarian factor(s) like the putative gonadotropinsurge inhibiting factor/attenuating factor exerts inhibitory effects on the amount of circulating gonadotropins
at the pituitary but rather at the hypothalamus level
itself. The steep increase in LH responsiveness occurs
only after the elimination of this inhibitory action by
GnRH [75]. Gonadal peptides may also be responsible
for the fact that the GnRH surge consistently continued
well beyond the surge of LH [76].
The importance of the episodic GnRH signal to the
pituitary gonadotropes was demonstrated over two
decades ago by Knobil and his colleagues. These studies
revealed that in the presence of a continuous GnRH
signal an episodic pituitary release of LH and FSH was
down-regulated to levels not compatible with fertility.
The continuous treatment by GnRH-I or GnRH-I
agonists was able, for example, to induce downregulatory effects in bovine pituitary gonadotrophs [77
81]. The examination of mechanisms of LH and FSH
biosynthesis revealed that the continuous treatment with
a GnRH-I agonist might influence gonadotropin
biosynthesis by a post-transcriptional mechanism
because the contents of both hormones were suppressed
to a greater degree than their beta-subunit mRNAs [82].
Recent studies in which the release of FSH and LH were
examined in pituitary portal or sinus cavernosus blood
samples have shown that, while there is a high degree of
synchrony between the pulsatile release of GnRH-I and
LH, FSH release is only associated with a small portion
of the GnRH pulses [13].
There are many experimental results which indicate
a different release pattern of LH and FSH during the
estrous cycle of untreated animals but the underlying
mechanisms are still unclear [52]. The existence of one
mechanism for the different regulation of LH and FSH
696
by a single neuroendocrine factor seems to be contradictory. High-frequency GnRH pulses favour LH

release, whereas low-frequency pulses favour FSH
release. This discrepancy was the reason to assume that
an additional peptide exists which releases specifically
FSH [83]. Among the natural GnRHs, both GnRH-II
[84,85] and lGnRH-III [86] or a closely related peptide
[46,87] have been suggested to be the putative FSH-RH
but there is neither a study confirming the presence of
GnRH-II in the pituitary portal blood [88] nor a
consensus over the functioning of lGnRH-III as FSHRH in mammals [11]. By applying a specific GnRH-I
antagonist in two sheep models, another group [89] was
able to demonstrate a constitutive component of GnRHI-independent basal LH release after termination of
pulses. But, more interestingly, a first evidence was
provided by the authors that an acute GnRH-Iindependent component of episodic FSH secretion
exists which may, probably be triggered by a selective
GnRH-II effect or by a hypothalamic compound still
unknown. In other studies [13,52], where a different
packaging of both gonadotropins in storage granules
within the gonadotrope cells was detected, constitutive
pathways of FSH and basal LH release as well as a
GnRH-regulated pathway of pulsatile LH release were
also explored.
The distribution of GnRH-I and its natural analogues
in both the same and different neurons and brain areas
may lead to the conclusion that there is a common or a
sequential release of related peptides. The distinguished
feature of GnRH-II is, for example, its wide distribution
in extrahypothalamic regions of the brain compared
with GnRH-I [21]. The more the interest is growing to
analyze the specific release patterns and to discover the
behavioral roles of GnRHs the more a need is arising to
develop suitable models [22]. Models may, for example,
involve animals that are energetically challenged by
food restriction. Such animals showed increases in the
number of GnRH-II immunoreactive cell bodies and
fiber dense area followed by a fast emptying of stored
peptide plus showing behavioral activity after refeeding
[31].
4. Reception of GnRH-I and its variants
Hypothalamic GnRH-I regulates the synthesis and
secretion of LH and FSH on pituitary gonadotrophs
through its receptor [90]. The density of the type-I
GnRHR on gonadotrophs is changing during various
stages of the estrous cycle [91]. Receptor concentrations
have been reported to increase up to day 18 of the
bovine estrous cycle [92] stimulated mainly by GnRH-I
itself and E2. Developing ovarian follicles produce

increasingly E2 that substitutes the GnRH effect and
maintains high abundance of GnRHR mRNA in the
preovulatory period. It was discussed that P4 exerts a
suppressive influence [91,93,94], therefore, maximal
GnRHR expression and maximal sensitivity of gonadotrophs to GnRH is probably triggered by decreased
circulating concentrations of P4 at luteolysis [95]. The
presence of a P4-responsive element in the 50 -flanking
region of the human GnRHR suggests, however, the
regulation of this gene by P4. As explored recently, the
physiological effects of P4 are mediated through two
receptor forms, the truncated form PR-A and PR-B.
Overexpression of PR-A was reported to decrease
GnRHR promoter activity both in pituitary and
placental cells but that of PR-B was found to exhibit
a cell-dependent transcriptional activity, e.g. to decrease
it only in pituitary cells [96].
From 1992/1993, since the initial isolation of the
cDNAs encoding the type-I GnRHR of the mouse
[97,98], rat [99,100], sheep [101,102], human
[103,104], cattle [105], pig [106] and, following this,
other species, a lot of studies were performed to
describe the molecular structure and organization of the
GnRHR gene. Mammalian pituitary type-I GnRHRs
share often over 80% AA identity. The cDNA of the
type-I GnRHR encodes, for example, a 327 AA protein
in mouse and rat, and a Lys residue more is present in
sheep and human [10]. Non-mammalian receptors show
not more than 4247% identity to those of mammals
and 5867% among each other, respectively [17].
The type-I GnRHR is a member of the G-proteincoupled receptor (GPCR) family which is characterized
by an extracellular N terminus and an intracellular C
terminus linked by seven transmembrane (7TM; TM1
TM7) helices. The helices are connected by each three
extracellular and intracellular loops [91,107,108].
GPCRs comprise a large superfamily of proteins; more
than 1000 different members of that are still known
[109]. Receptor binding activates two specific GTPbinding proteins (Gq/G11), which stimulate increased
phosphoinositol turnover by activating phospholipase C
(PLC). This enzyme leads to the generation of several
second messengers [110]. Among these, diacylglycerol
(DG) and inositol 1,4,5-tris-phosphate (IP3) are
critically important. DG leads to activation of protein
kinase C (PKC), and IP3 releases Ca2+ from intracellular pools [74]. Both events result in gonadotropin
synthesis, which is realized across the stimulation of the
steroidogenic factor 1 (SF-1) [111,112], followed by
secretion of LH and FSH. It has been demonstrated that
the GnRH signal transduction pathway involves an
increase in cAMP and an activation of members of the

mitogen-activated protein kinase (MAPK) family
[74,110]. To help understanding the molecular mechanisms involved in transcriptional regulation of the receptor
gene, the 50 flanking region of the type-I GnRHR has been
isolated, and there were explored several DNA regions
which are responsible for both basal expression and
GnRH-I-mediated homologous regulation of this gene in
pituitary cells [113]. The type-I GnRHR has a relatively
short third intracellular loop, and it lacks a C terminal tail
[110]. Because the tail is unique among GPCRs, its loss
during evolution should be discussed. The structural
features described may be responsible for the relative
resistance of the type-I GnRHR to rapid homologous
receptor desensitization and slow internalization by
GnRH-I agonist-induced phosphorylation or binding barrestin by sustained stimulation [114].
However, the presence of more than one forms of
GnRH in the same species implies the co-evolution of
cognate receptors. In all, three GnRH peptides and three
cognate receptors have been yet identified with distinct
distributions and functions [17]. Two or three different
types of GnRHR have been indeed identified in nonmammalian species like fish and frog [20], but also in
Macaca mulatta [115,116]. In contrast, only one
functional GnRHR gene, the type-I GnRH gene, has
been identified in humans. Some findings suggested that
a type-II GnRHR gene has arisen during vertebrate
evolution, is also present but vestigial in the human due to
the transcription of the opposite DNA strand to antisense
RNA [117]. The gene encoding the type-II GnRHR is,
however, functional in chimpanzee but partially or
completely silenced in a range of other mammals [33].
Antisera to one domain of the human type-II receptor, for
example, revealed immunoreactivity in pituitary and
brain cells of the human, rhesus monkey, sheep and
mouse [21]. The primate type-II GnRHR AA sequences
share 60% identity with amphibian type-II GnRHRs and
40% identity with the human type-I GnRHR [88]. That
means that the structure of monkey type-II GnRHR
resembles more closely non-mammalian types of
GnRHRs than mammalian type-I GnRHRs [20]. Likewise, non-mammalian GnRHRs contain also a Cterminal cytoplasmatic tail, and both groups of receptors
have conserved Asp2.50/Asp7.49 residues, while mammalian GnRHRs contain Asn2.50/Asp7.49 at these positions
[118]. It was shown by mutation products of the mouse
type-II receptor that Asp7.49 in TM7 is an essential
component of ligand-mediated receptor activation and
the TM2 Asn2.50 is essential for configuring and
expression of the receptor [17]. Finally, non-mammalian
and monkey type-II GnRHRs are more sensitive to
697
GnRH-II than GnRH-I [30,119]. Type-II receptors are

highly selective for GnRH-II, e.g. GnRH-II is approximately 400-fold more potent at type-II GnRHR than
type-I receptors [17] and has approximately 10% of
the activity of GnRH-I at the type-I receptor [30],
respectively.
In addition to the gonadotropes, type-I GnRHRs are
also expressed in many other tissues, e.g. breast, gonads,
the central nervous system, and some neoplastic tissues
[6,114,120123]. The presence of GnRH-I and type-I
receptors in the gonads of various vertebrate species,
including mammals, may reflect a direct regulation of the
gonads as an early evolved function, and the neuroendocrine role in regulating the pituitary as a later
evolutionary development [11]. However, unlike the
hypothalamus and pituitary, the regulation of GnRH-I
and its receptor in the ovary is poorly understood [12]. In
human placenta, where GnRH-I is thought to play roles in
both growth and function, the expression of type-I
receptors is regulated by an autocrine mechanism [124].
Recently, it was shown, that GnRH-I and GnRH-II are
coexpressed in the first-trimester decidua, suggesting
biological effects within and between maternal and fetal
cellular compartments [125]. As mentioned before, the
type-II GnRHR has been cloned from various vertebrate
species, including New and Old World primates. The
human gene homologue of this receptor is considered as
vestigial receptor, as reported [117], is frame-shifted and
has a different stop codon, and it appears that GnRH-II
signalling occurs through the type-I receptor [17]. A
growing number of extrapituitary GnRH-II actions in
humans have been demonstrated although a full-length
type-II receptor transcript has not yet been identified
[115]. Likewise, it is absent from chimpanzee, cow,
horse, sheep, rat and mouse in spite of its presence in
other species, e.g. pig [11]. This challenges the question if
there is expressed a functional type-II receptor protein
expression in cells lacking the type-I receptor. It was
shown that the antiproliferative effect of GnRH-II on
human cancer cells is not mediated through the type-I
receptor like that of a GnRH antagonist [126]. The data
are in accord with a report from [127] demonstrating that
the human type-II GnRHR is functional, and its splice
variant determines the direction of the cellular response
to GnRH stimulation. More recently, an immunohistological study using a polyclonal antiserum against the
putative human GnRH-II receptor demonstrated the
existence of a GnRH-II receptor-like protein in human
placenta and in cancers of human reproductive organs
[128].
The sequences of the pig and monkey type-II
GnRHRs are 91% identical as well as their functional
698
Fig. 3. Topography of amino acid sequences of the three pig GnRH receptors type-I GnRHR (A), type-II GnRHR-5TM (B) and type-II GnRHR7TM (C). Adapted to Weesner and Matteri [106] and Neill et al. [130].
properties, e.g. in terms of stimulating the IP3 production

by GnRH-I and GnRH-II, respectively [30]. Interestingly, further variants of the type-II GnRHR exist in
sheep and cattle which do not appear to encode functional
7TM GPCRs. Similar observations were made in human
and pigs where receptor forms have been explored which
showed a shortened structure (Fig. 3) [30,88,129,130].
5. Hypophyseal and extrahypophyseal effects of
natural GnRHs
In invertebrates, which have no pituitary gland, the
diversity of anatomical distribution patterns observed for
GnRH or GnRH-like factors suggests that GnRHs may
have multiple functions. One of them could be related to
stimulation of reproduction by a direct action on the
gonads [11,15,131]. Such functions explored for GnRH
variants except GnRH-I in vertebrates would be
evolutionarily old whereas the evolutionarily younger
GnRH-I became responsive for specific tasks within the
HPG axis. The questions are if, in higher vertebrates, both
GnRH-I exerts functions other than stimulation of
pituitary and if GnRHs exert functions included
stimulation of gonadotropin release. Now, it is commonly
accepted that GnRH-I is integrated in some important
functions which fall into three categories [130]:
gonadotropin secretion;
sexual behavior;
regulation of peripheral reproductive tissues.
For a few decades, hypothalamic GnRH-I has been

assumed to be sufficient to control synthesis and release
of gonadotropins and sexual behavior, hence reproductive function. Furthermore, it was suggested that the
interactions of GnRH-I with ovarian steroids at the
pituitary level are responsible for the final regulation of
LH and FSH release. As reviewed above, an increasing
number of peptides have been observed, however, to
affect gonadotropin activity during the following
decades. None of these factors has gained an
importance equal to that of GnRH-I. All data available
suggest that differential synthesis and release of
gonadotropins is caused by an altered pattern of
pulsatile GnRH-I secretion and triggered by activation
of pituitary type-I GnRHR [74].
Endogenous sources for GnRH and GnRH-like
factors were found in manifold tissues. The fast
destruction of the releasing hormone of hypothalamic
origin by specific peptidases might lessen peripheral
effects of them. However, GnRH-I influences the
functions of other organs, such as the breast, placenta,
and ovary, in addition to its actions in the brain and
pituitary. Extrapituitary actions of GnRH-I which have
been manifold documented suggest that there is a
functioning GnRH/GnRHR system in these organs.
There is evidence for a paracrine/autocrine role of
GnRH-I in the regulation of ovarian processes like
follicular atresia and luteinization [132134]. Several
findings suggest that GnRH-I plays regulatory roles
in processes prerequisite for decidualization and
trophoblast invasion in humans [115]. Moreover, GnRHI plays various neuromodulatory roles: it is present in the
nervus terminalis, a neural plexus in the chemosensory
mucosa of the nasal cavity, where it has obviously the
function to modify olfactory information, perhaps at
reproductively auspicious times [28]. The physiological
roles of GnRH-I forms remain poorly understood until
now [88]. Most information has been gained, however, on
GnRH-II, where the specific conformation stabilizes the
peptide compared to GnRH-I. The conservation of the
GnRH-II structure >500 million years, unique location,
and differential expression levels of GnRH-II the type-II
receptor within and outside the brain in a distinct species
suggest that it has a variety of reproductive and nonreproductive functions [8,10,21,43,88] (Table 2).
As mentioned above, GnRH-II has a low affinity to the
type-I receptor. Therefore, it seems to be reasonable to
reassess whether functions that have been ascribed to
GnRH-I are might be caused by GnRH-II [130]. The
neuromodulatory roles outlined for GnRH-I were also
found for GnRH-II [18,125]. The conservation of the
GnRH-II structure may indicate more a function as
neurotransmitter which is involved in sexual behavior,
than that of a hormone which induces gonadotropin
release [21]. However, the only established function of
GnRH-II is the inhibition of M currents (K+ channels) in
amphibian sympathetic ganglia mediated by binding to a
receptor that is a homologue to the primate type-II
GnRHR [21,134]. This function may support a role of
GnRH-II as neuromodulator that seems to be a common
and old function of GnRH variants. It has been shown, for
example, that these peptides are able to stimulate
simultaneous spawning of individuals in a population,
and in this way assure more successful fertilization in
species that release their gametes into the water in which
Table 2
Tissue distribution and proposed physiological functions for GnRH-II
Tissue
Proposed function
Central and peripheral

nervous system
Mediobasal hypothalamus
Limbic structures
Neuromodulation
Control of gonadotropin secretion
Stimulation of reproductive behavior
Placenta
Endometrium
Breast
Ovary
Regulation of endocrine functions
Tumors of the female

reproductive tract
Normal T cells,
tumor T cells
Inhibition of cell proliferation
Adapted to Limonta et al. [8].
Stimulation of cell
adhesion and migration
699
they live [15]. In vertebrates, however, there is a high colocalization of type-I receptors and type-II receptors in
pituitary gonadotropes. Therefore, GnRH-I and GnRH-II
may operate in concert to control the release of FSH and
LH. Silencing of the type-II GnRHR can be, however,
accommodated by GnRH-II signalling through the type-I
receptor with a distinctly different profile [11].
Is one of the GnRHs able, however, to act as an
specific FSH-releasing hormone (FSH-RH)? This issue
became the subject of speculation from the beginning of
the experimental GnRH story [83,135,136]. An FSHRH must be capable for selectively stimulating FSH
over LH or at least be a more potent releaser for FSH
than of LH which should result in a discordant FSH
secretion. GnRH-II has been designated as FSH-RH
[84,85]. On the other hand there is no study confirming
that the peptide is present in the pituitary portal blood
[137]. The presence, however, must be seen as a
prerequisite to exert a gonadotropin-releasing function.
Other studies using rat hemi-pituitary cultures showed
that only lGnRH-III stimulates FSH release at much
lower doses than those required for LH [86,138]. More
recent results confirmed the conclusion that lGnRH-III
or a closely related peptide was really the wanted FSHRH [46,87,139]. However, there is no consensus if
lGnRH-III functions as FSH-RH or not in mammals
[11] because others [29,140,141] were not able either to
isolate lGnRH-III from various mammalian brains or to
stimulate specifically FSH secretion by this variant.
Recently, it was summarized that lGnRH-III has no
endocrine activity in mammals [142]. Therefore, it
seems to be necessary to proof the question again in
animal models, e.g. in sheep, in which the pituitary is
disconnected from the brain. This model would
eliminate problems in differentiating effects caused
by other peptides [21]. Apart from the gonadotropinreleasing effects by GnRH-I to GnRH-III, and [Hyp9]GnRH, it was reported that wfGnRH (Table 1) increased
gonadotropin/TSHalpha subunit RNA expression in
dispersed rainbow trout pituitary cells [38] whereas
most of GnRH variants showed a very low activity in
stimulating gonadotropin release or ovulation [3].
For GnRH-II a role as an coordinator between food
intake and energetic condition, respectively, and reproductive behavior was hypothesized. This function of
GnRH-II may result in mating under optimized conditions [31,143]. It would be interesting to examine the
level of type-II GnRHRs expressed in that species and to
test these effects of GnRH-II in other mammals. Both
GnRH systems, the GnRH-I/type-IGnRHR and the
GnRH-II/type-II GnRHR system, likely evolved together
and act in a synergistic manner. Because nutrition and
700
of the inherited genetic potential [144]. The development of systems to control ovarian function and
reproductive efficiency with GnRHs and other pharmaceutical agents has to be founded on an understanding of induced physiological effects and ability to
capture any advantage by good management of the farm
unit [145]. The pharmacological basis for the therapeutic use of GnRH derives from its physiological
effect of stimulating gonadotropin release [146]. The
use of GnRH-I and synthetic analogues is common in
domestic animal production systems. The evaluation of
agonist potency depends largely on the model used and
wide varying potencies are reported for the same
agonist. The design of analogues has focused on
improving the receptor-binding and subsequent activation for agonists as well as on their increased resistance
to degradation by peptidases. In veterinary medicine the
most widely used agonists are the natural decapeptide,
buserelin and deslorelin [146]. Likewise, other synthetic analogues have reached practical importance
(Table 3).
The single treatment by a small dose of the GnRH-I
agonist or its sustained release in low quantities will
induce, after binding to the receptor and internalization
of the ligand/receptor complex, a transient insensitivity
to stimulation in gonadotrophs. The type-I GnRHR is
replenished within several hours and this restores the
responsiveness of cells to GnRH. Unlike that antagonists may not provoke the initial stimulatory effect of
reproduction are closely linked, it may be plausible that

during evolution first the more ancient GnRH form, i.e.
GnRH-II, served all functions that coordinated energy
and reproduction. Later GnRH-I usurped many of the
non-behavioral functions as the interactions between the
pituitary and gonads in mammals.
It may be a disadvantage that most of the studies on
the HPG axis were conducted in domesticated, well-fed
laboratory mammals which may or may not even
produce GnRH-II. Furthermore, it should be not
surprising that results of examinations of natural GnRH
variants in vivo and in vitro may differ from one species
or cell type to another. While it is becoming evident that
some species do not have a conventional type-II
GnRHR system, specific GnRH-II responses have been
observed in certain cell types. To solve this problem, the
demonstration of a functional GnRH-II/type-II receptor
system in cells lacking the type-I-receptor is needed
[115]. Recently, such system was explored that exists in
human endometrial, ovarian and breast cancer cells
probably enabling the therapeutic use of GnRH-II to
reduce proliferation of those not mediated by the type-I
receptor [126].
6. Use of GnRH-I and its natural forms in farm
animals
There is a growing interest to increase the efficiency
of reproductive performances of farm animals, towards
Table 3
Amino acid sequences of selected GnRH-I agonists and antagonists used/recommended for use in humans and farm animals
Amino acid
1
10
GnRH-I
pGlu
His
Trp
Ser
Tyr
Gly
Leu
Arg
Pro
Gly.NH2
Agonists
Lupron
Zoladex
Supprelin
Synarel
Triptorelin
Buserelin
Goserelin
Deslorelin
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
pGlu
His
His
His
His
His
His
His
His
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Trp
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
D
D
D
D
D
D
D
D
Leu
Leu
Leu
Leu
Leu
Leu
Leu
Leu
Arg
Arg
Arg
Arg
Arg
Arg
Arg
Arg
Pro NEt
Pro
Pro
Pro
Pro
Pro NEt
Pro
Pro NEt
Antagonists
Cetrorelix
Ganirelix
Abarelix
Antide
Teverelix
FE 200486
Nal-Glu
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
Ser
Ser
Ser
Ser
Ser
Ser
Ser
Tyr
Tyr
N Me Tyr
Lys (Nic)
Tyr
Aph (Hor)
Arg
D Cit
D hArg (Et)2
D Asn
D Cit
D hCit
D Aph (Cba)
D Glu (AA)
Leu
Leu
Leu
Leu
Leu
Leu
Leu
Arg
D hArg (Et)2
Lys (iPr)
Lys (iPr)
Lys (iPr)
Lys (iPr)
Arg
Pro
Pro
Pro
Pro
Pro
Pro
Pro
Nal
Nal
Nal
Nal
Nal
Nal
Nal
Cpa
Cpa
Cpa
Cpa
Cpa
Cpa
Cpa
Pal
Pal
Pal
Pal
Pal
Pal
Pal
Leu
Ser (tBu)
His (ImBzl)
Nal
Trp
Ser (tBu)
Ser (tBu)
Trp
Bold letters: primary structure of GnRH-I and identical amino acids in analogues. Adapted to Millar et al. [17].
Gly.NH2
Gly.NH2
Gly.NH2
Gly.NH2
AzGly
D Ala.
D Ala.
D Ala.
D Ala.
D Ala.
D Ala.
D Ala.
NH2
NH2
NH2
NH2
NH2
NH2
NH2
agonists and their blocking effects are immediate but

just as reversible [147].
Previously, one of the main objectives to use GnRH-I
and its synthetic agonists was to induce in females
reduced fertility or even infertility using the LHreleasing and ovulation-inducing properties. The
development of pro-fertility treatments resulted in
several therapies, e.g. induction of ovulation, treatment
of cystic ovarian disease and prevention of embryonic
mortality. Numerous studies have been carried out with
GnRH-I and agonists in different climates, production
systems, reproduction status, etc. and sometimes
combined with other hormonal treatments. In this
context it is sometimes difficult to draw general
conclusions on treatment efficacy in several species
[146]. For several reasons the situation in the GnRHtreated cattle needs special interest but conclusions are
to drawn parallel for sheep, horses and pigs.
GnRH-I agonists originally developed to treat
infertility show paradoxically inhibited reproduction
when given in high doses or even continuously. This
effect is exploited in anti-fertility methods of treatment.
There are, however, different ways that GnRH-I
analogues can be employed to inhibit reproduction
by direct suppression of the HPG axis at the level of the
gonadotroph: (1) chronic administration of agonists
causing down-regulation of type-I GnRHR and desensitization of pituitary gonadotrophs; (2) immunization
against GnRH-I resulting in the neutralization of
GnRH-I in the hypophyseal portal blood by antibodies
and (3) the use of antagonists to block receptors to
occupancy by endogenous GnRH-I [147].
Among the pro-fertility treatments the therapy of
bovine cystic ovarian disease by GnRH was undertaken
in numerous studies [145,148150]. Although commonly used in veterinary practice the fertility of treated
cattle remains very poor after stimulating ovulation/
luteinisation of a new follicle and luteinisation of the
cyst. A better understanding of the syndrome is
probably required to improve fertility and not only to
restore normal fertility [146]. Another complex of
treatments by GnRH-I is directed to the support of
ovulation process. Data from treatments of various
species underline the importance of additional GnRH
on the day of insemination to improve the chances of
successful pregnancy. It is the common aim of the
treatment to stimulate luteinisation and early production
of luteal progesterone [151155]. When comparing the
effects of different studies it was summarized [146] that
the lower the background fertility in the herd, the higher
the percentage improvement. Given a satisfying fertility
in the herd the results may be equivocally.
701
In cattle but also in other species numerous

experiments were performed to enhance the luteal
function and improve the pregnancy rate by a GnRH
treatment approximately during the periods of maternal
recognition of pregnancy [156161]. Recently, it was
summarized that the balance of different data suggests
that post-insemination GnRH treatments are beneficial
but exact validations of physiological and environmental variables have to be executed in each treated
species [146]. A further aim of GnRH treatment is
directed to override the delayed resumption of ovarian
cyclicity in cows post-partum. It was stated [162] that
research on this topic seems to have lapsed in the last
decade when real time ultrasound was available for onfarm diagnosis of ovarian status.
The treatment of seasonally anestrous animals, e.g.
sheep, by GnRH has reached only a limited importance
although scientifically solved by applying multiple lowdose injections of an agonist [163,164]. Reasons were
seen in the necessity to prime the animals by
progesterone to simulate a luteal-like period of cycle
followed by the peptide treatment which will increase
unfavourably the costs of treatment.
Use of GnRH as an integral part of synchronising
regimens where is given 7 days before PG an then again
4860 h after PG appears to be effective in increasing
the synchrony of ovulation in controlled breeding
programmes [165170]. Whereas the first injection is
important for the prolongation of luteal phases in those
animals treated late in the cycle, the main synchronising
effect seems result from the second GnRH injection.
This injection advanced the timing of ovulation and the
subsequent rise in progesterone concentrations by an
average of 24 h relative to cows just receiving a GnRHPG regimen [146].
The other complex of methods that use GnRH-I
analogues is summarized as anti-fertility technologies.
Long-term fertility control agents are of interest for the
management of reproduction in humans, domestic
animals and wildlife. This topic is important in the
management of farm animals but from both the
behavioral and fertility standpoint, as is the case with
domestic dogs and cats [147]. A first group of methods
is using the paradox effect of continuous GnRH on
reproductive function. The continuous availability of
the peptide is reached mainly by depot formulations.
The desensitization of the gonadotrophes is followed
by a decline in ovarian and testicular functions,
respectively. This phenomenon is extensively applied
in clinical medicine for the treatment of a wide range
of disease [12]. Depot GnRH-I agonists are now
increasingly used in animal treatments [171174].
702
Recently [147] it was reviewed that agonists when

released over periods of some months showed a high
contraceptive rate both in veterinary regimes to treat
farm and domestic animals. The fertility control by
GnRH-I agonists has some advantages when compared
with traditional surgical sterilization methods. One
advantage is that contraception is affected after a single
injection without the need for use of adjuvants.
Numerous studies demonstrated a positive relationship
between the dose of agonist and the duration of
suppression but the reasons are still unknown. Recent
results indicated that a continuous influence of a depot
GnRH-I agonist over a period of more than 1 week will
impair the development of bovine follicles and oocytes
[175].
Moreover, a wide range of variation was observed
between individual animals in the interval to resumption
of oestrous cycles after treatment and in the function of
testes, respectively. A recent review [176] discussed the
effects observed in growing and mature boars of a longacting agonist treatment. Results of various studies
[177,178] suggested that the treatment may be an
effective means of reducing the taint in boar meat. In
contrast to the response detected in most other species
results were described that a GnRH-I agonist treatment
induced an increase in the reproductive function. The
treatment may be, for example, effective to accelerate
puberty in calves [176,179].
Other possibilities to control fertility by GnRH are the
treatments by antagonists and the immunization against
the peptide resulting in its neutralisation in the portal
blood by antibodies. Both methods are in the phase of
development but they may have potential. The immunoneutralisation of endogenous GnRH-I may prove to be
an useful management tool in keeping both female and
male animals [176]. The method has the advantage that it
does not have a stimulatory acute phase [180185]. One
disadvantage of vaccination is, however, the inconsistent
and variable immune response of treated animals. Novel
types of anti-GnRH vaccines are now under development
to reduce the variation.
GnRH-I antagonists (Table 3) also inhibit the
reproductive system through competition with endogenous peptide but the doses required to block
gonadotropin release are higher than that of the
comparable agonist treatment [186191]. Efficient
delivering systems or the development of non-peptide
orally active antagonists are likely to replace agonists as
they avoid the undesirable stimulation that precedes
desensitization [12]. Until acceptable technologies are
available, the use of GnRH-I antagonists is especially to
recommend for short-term treatments, e.g. down-
regulation of the pituitary during IVF treatment regimes

[147].
In brief, GnRH-based methods to manage fertility in
farm animals have potential but the widespread
application of these technologies is limited to date.
Compared with the possibilities to apply GnRH-I and its
synthetic analogues knowledge is only scarce on
possibilities for the natural GnRH-I analogues. The
main reason is that the physiological roles of GnRH-II
and its receptor, and the roles of other pairs, relative to
GnRH-I and its receptor are unknown [30]. Also, other
facts may contribute, like the poor uniformity of
occurrence [192] and reception [33] of GnRHs in
mammals which make the development of suitable
models more difficult. It seems to be nearly impossible
to evaluate in vivo-effects of GnRHs beside that of
GnRH-I. From data available at present, the following
hypotheses should be executed in various models:
Natural GnRHs unlike GnRH-I present in farm
animals are residues of a long developmental process.
They have no or less independent importance for
basic functions of mammalian reproduction. GnRHs
may intensify GnRH-I-mediated effects within the
HPG axis. The contributions of GnRHs are still
unknown but may vary between species, periods of
the reproductive cycle, tissues and environmental
factors, etc.
GnRHs like GnRH-II, lGnRH-III or GnRH-III have
functions within the neuroendocrine regulation of
reproduction distinct from GnRH-I functions as
discussed for the specific release of FSH [84
87,139,193]. This is supported by the fact that
chronic administration of a GnRH-I shows a
differential response of pituitary gland and gonads
to the medication [194], even in ruminants [156].
GnRHs unlike GnRH-I show specific effects which
result from the past like the combination of external
factors from the environment with neuroendocrine
mechanisms of regulation of reproductive function. In
mammals, where, for example, GnRH-II is expressed
at significantly higher levels outside the brain, the
peptide may participate, more than GnRH-I [10] in
the induction of mating behavior. Ovarian steroids
and their antagonists were reported to affect
differentially the expression of GnRH-I and GnRHII in human granulosa cells at the transcriptional level
[195]. Both GnRH-II [9] and lGnRH-III [142] showed
a direct antiproliferative effect on various cancer cell
lines. Superactive analogues of that may, therefore,
useful in specific therapeutic regimes in humans,
instead of long-term administered GnRH-I agonists
[9]. An inclusion of GnRHs in treatment schedules of

farm animals seems to be possible.
To execute the preceding hypotheses, some general
premises should be realized. The first step is to complete
the listing of presence of various GnRH forms in one
species, in one tissue or expressed in one cell type. Next,
the spectrum of analytical methods to characterize
highly specifically the biosynthesis, release of single
variants in vivo and in vitro, and reception has to be
replenished. Thus, animal models have to be created
which may demonstrate specific effects of GnRH
variants independent on the other forms, in particular
GnRH-I, which may effect negligible low [21].
However, the function of GnRH-II as coordinator
between nutrition and reproduction [143] should be
explored in experimental studies on animals fed at
different levels. Generally, development and use of
potent synthetic analogues (agonists and antagonists) of
promising GnRHs-like [D-Ala6]-GnRH-II and Trptorelix-1 [20] and [D-Arg6]-GnRH-II-aza-Gly(10)-NH2
[196] may contribute to the exploration of functions of
non-mammalian GnRHs in mammals. On the basis of
these diverse studies a further progress in the
development of effective and animal friendly applications for natural GnRHs might be expected.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
References
[19]
[1] Matsuo H, Baba Y, Nair RMG, Arimura A, Schally AV.
Structure of the porcine LH-and FSH-releasing hormone. I.
The proposed amino acid sequence. Biochem Biophys Res
Commun 1971;43:13349.
[2] Amoss M, Burgus R, Blackwell R, Vale W, Fellows R,
Guillemin R. Purification, amino acid composition and nterminus of the hypothalamic luteinizing hormone releasing
factor (lrf) of ovine origin. Biochem Biophys Res Commun
1971;44:20510.
[3] Sherwood NM, Lovejoy DA, Coe IR. Origin of mammalian
gonadotropin-releasing hormones. Endocr Rev 1993;14:
24154.
[4] Casan EM, Raga F, Bonilla-Musoles F, Polan ML. Human
oviductal gonadotropin-releasing hormone: possible implications in fertilization, early embryonic development, and
implantation. J Clin Endocrinol Metab 2000;85:137781.
[5] Krsmanovic LZ, Martinez-Fuentes J, Arora KK, Mores N,
Tomic M, Stojilkovic SS, et al. Local regulation of gonadotroph
function by pituitary gonadotropin-releasing hormone. Endocrinology 2000;141:118795.
[6] Grundker C, Gunthert AR, Westphalen S, Emons G. Biology of
the gonadotropin-releasing hormone system in gynaecological
cancers. Euro J Endocrinol 2002;146:114.
[7] Leung PC, Cheng CK, Zhu XM. Multi-factorial role of GnRH-I
and GnRH-II in the human ovary. Mol Cell Endocrinol
2003;202:14553.
[8] Limonta P, Moretti RM, Marelli MM, Motta M. The biology of
gonadotropin hormone-releasing hormone: role in the control
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
703
of tumor growth and progression in humans. Front Neuroendocrinol 2003;24:27995.

Emons G, Grundker C, Gunthert AR, Westphalen S, Kavanagh
J, Verschraegen C. GnRH antagonists in the treatment of
gynecological and breast cancers. Endocrine Relat Cancer
2003;10:2919.
Kang SK, Choi KC, Yang HS, Leung PCK. Potential role of
gonadotrophin-releasing hormone (GnRH-I) and GnRH-II in
the ovary and the ovarian cancer. Endocrine Relat cancer 2003;
10:16977.
Guillemin R. Hypothalamic hormones a.k.a. hypothalamic
releasing factors. J Endocrinol 2005;184:1128.
Millar RP. GnRHs and GnRH receptors. Anim Reprod Sci
2005;88:528.
Pawson AJ, McNeilly AS. The pituitary effects of GnRH. Anim
Reprod Sci 2005;88:7594.
Sealfon SC, Weinstein H, Millar RP. Molecular mechanisms of
ligand interaction with the gonadotropin-releasing hormone
receptor. Endocr Rev 1997;18:180205.
Gorbman A, Sower SA. Evolution of the role of GnRH in
animal (Metazoan) biology. Gen Comp Endocrinol 2003;134:
20713.
Amano M, Oka Y, Kitamura S, Ikuta K, Aida K. Ontogenetic
development of salmon GnRH and chicken GnRH-II systems in
the brain of masu salmon (Oncorhynchus masou). Cell Tissue
Res 1998;293:42734.
Millar R, Lu Z-L, Pawson AJ, Flanagan CA, Morgan K,
Maudsley SR. Gonadotropin-releasing hormone receptors.
Endocr Rev 2004;25:23575.
Okubo K, Aida K. Gonadotropin-releasing hormone gene
products downregulate the expression of their neighboring
genes that encode protein tyrosine phosphatases a and e.
Biochem Biophys Res Commun 2003;312:5316.
Cheon KW, Lee HS, Parhar I, Kang IS. Expression of the
second isoform of gonadotrophin-releasing hormone (GnRHII) in human endometrium throughout the menstrual cycle.
Molec Hum Reprod 2001;7:44752.
Maiti K, Li JH, Wang AF, Acharjee S, Kim WP, Im WB, et al.
GnRH-II analogs for selective activation and inhibition of nonmammalian and type-II mammalian GnRH receptors. Mol
Cells 2003;16:1739.
Millar RP. GnRH II and type II GnRH receptors. Trends
Endocrinol Metab 2003;14:3543.
Ramakrishnappa N, Rajamahendran R, Lin YM, Leung PCK.
GnRH in non-hypothalamic tissues. Anim Reprod Sci 2005;
88:95113.
Clarke IJ, Pompolo S. Synthesis and secretion of GnRH. Anim
Reprod Sci 2005;88:2955.
Amano M, Takahashi A, Yamanome T, Okubo K, Aida K,
Yamamori K. Molecular cloning of three cDNAs encoding
different GnRHs in the brain of barfin flounder. Gen Comp
Endocrinol 2002;126:32533.
Kleine B, Kienle A, Poettich M, Wolfahrt S, Jarry H, Rossmanith WG. Analysis of ultrashort feedback regulation in human
placental synthesis and secretion of GnRH by human trophoblastic cells. Horm Metab Res 2000;32:21623.
Rissman EF. Behavioral regulation of gonadotropin-releasing
hormone. Biol Reprod 1996;54:4139.
Bless EP, Walker HJ, Yu KW, Knoll JG, Moenter SM,
Schwarting GA, et al. Live view of gonadotropin-releasing
hormone containing neuron migration. Endocrinology 2005;
146:4638.
704
[28] Wirsig-Wiechmann CR. Function of gonadotropin-releasing

hormone in olfaction. Keio J Med 2001;50:815.
[29] Montaner AD, Mongiat L, Lux-Lantos VAR, Park M, Fischer
WH, Craig AG, et al. Structure and biological activity of
gonadotropin-releasing hormone isoforms isolated from rat
and hamster brains. Neuroendocrinology 2001;74:20212.
[30] Neill JD. Minireview: GnRH and GnRH receptor genes in the
human genome. Endocrinology 2002;143:73743.
[31] Temple JL, Millar RP, Rissman EF. An evolutionarily conserved form of gonadotropin-releasing hormone coordinates
energy and reproductive behavior. Endocrinology 2003;144:
139.
[32] Hiney JK, Sower SA, Yu WH, McCann SM, Dees WL.
Gonadotropin-relasing hormone neurons in the preoptichypothalamic region of the rat contain lamprey gonadotropin-releasing hormone III, mammalian luteinizing hormonereleasing hormone, or both peptides. Proc Natl Acad Sci USA
2002;99:238691.
[33] Morgan K, Millar RP. Evolution of GnRH ligand precursors
and GnRH receptors in protochordate and vertebrate species.
Gen Comp Endocrinol 2004;139:1917.
[34] Iwakoshi E, Takuwa-Kuroda K, Fujisawa Y, Hisada M, Ukena
K, Tsutsui K, et al. Isolation and characterization of a GnRHlike peptide from octopus vulgaris. Biochem Biophys Res
Commun 2002;291:118793.
[35] Gautron JP, Pattou E, Bauer K, Kordon C. Preferential distribution of C-terminal fragments of [hydroxyproline9]LHRH
in the rat hypocampus and olfactory bulb. Neuroendocrinology
1993;58:24050.
[36] Montaner AD, Park M, Fischer WH, Craig AG, Chang JP,
Somoza GM, et al. Primary structure of a novel gonadotropinreleasing hormone in the brain of teleost, pejerrey. Endocrinology 2001;142:145360.
[37] Yamanaka C, Lebrethon MC, Vandersmissen E, Gerard A,
Purnelle G, Lemaitre M, et al. Early prepubertal ontogeny of
pulsatile gonadotropin-releasing hormone (GnRH) secretion: I.
Inhibitory autofeedback control through prolyl endopeptidase
degradation of GnRH. Endocrinology 1999;140:460915.
[38] Adams BA, Vickers ED, Warby C, Park M, Fischer WH, Craig
AG, et al. Three forms of gonadotropin-releasing hormone,
including a novel form, in a basal salmonid, Coregonus clupeaformis. Biol Reprod 2002;67:2329.
[39] Adelman JP, Mason AJ, Hayflick JS, Seeburg PH. Isolation of
the gene and hypothalamic cDNA for the common precursor of
gonadotropin-releasing hormone and prolactin-inhibiting factor in human and rat. Proc Natl Acad Sci USA 1986;83:17983.
[40] White RB, Eisen JA, Kasten TL, Fernald RD. Second gene for
gonadotropin-releasing hormone in humans. Proc Natl Acad
Sci USA 1998;95:3059.
[41] Lescheid DW, Terasawa E, Abler LA, Urbanski HF, Warby
CM, Millar RP, et al. A second form of gonadotropin-releasing
hormone (GnRH) with characteristics of chicken GnRH-II
is present in the primate brain. Endocrinology 1997;138:
561829.
[42] Densmore VS, Urbanski HF. Relative effect of gonadotropinreleasing hormone (GnRH)-I and GnRH-II on gonadotropin
release. J Clin Endocrinol Metab 2003;88:212634.
[43] Pawson AJ, Morgan K, Maudsley SR, Millar RP. Type II
gonadotrophin-releasing-hormone (GnRH-II) in reproductive
biology. Reproduction 2003;126:2718.
[44] Kasten TL, White SA, Norton TT, Bond CT, Adelman JP,
Fernald RD. Characterization of two new preproGnRH mRNAs
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
in the tree shrew: first evidence for mesencephalic GnRH

expression in a placental mammal. Gen Comp Endocrinol
1996;104:719.
Rissman EF, Alones V, Craig-Veit CB, Millam JR. Distribution
of chicken II gonadotropin-releasing hormone in mammalian
brain. J Comp Neurol 1995;357:52431.
Yu WH, Karanth S, Sower SA, Parlow AFP, McCann SM. The
similarity of FSH-releasing factor to lamprey gonadotropinreleasing hormone III (l-GnRH-III). Proc Soc Exper Biol Med
2000;224:8792.
Yahalom D, Chen A, Ben-Aroya N, Rahimipour S, Kaganovsky E, Okon E, et al. The gonadotropin-releasing hormone family of neuropeptides in the brain of human, bovine
and rat; identification of a third isoform. FEBS Lett 1999;
463:28994.
Moenter SM, DeFazio RA, Pitts GR, Nunemaker CS. Mechanisms underlying episodic gonadotropin-releasing hormone
secretion. Front Neuroendocrinol 2003;24:7993.
Piva F, Zanisi M, Motta M, Martini L. Ultrashort control of
hypothalamic hormones secretion: a history. J Endocrinol
Invest 2004;27(Suppl. 6):6872.
McCann SM, Kimura M, Walczewska A, Karranth S, Rettori V,
Yu WH. Hypothalamic control of FSH and LH by FSH-RF,
LHRH, cytokines, leptin and nitric oxide. Neuroimmunomodulation 1998;5:193202.
Nunemaker CS, Straume M, Defazio RA, Moenter SM. Gonadotropin-releasing hormone neurons generate interacting
rhythms in multiple time domains. Endocrinology 2003;144:
82331.
McNeilly AS, Crawford JL, Taragnat C, Nicol L, McNeilly JR.
The differential secretion of FSH and LH: regulation through
genes, feedback and packaging. Reprod Suppl 2003;61:463
76.
Weesner GD, Harms PG, McArthur NH, Wilson JM, Forrest
DW, Wu TJ, et al. Luteinizing hormone-releasing hormone
gene expression in the bovine brain: anatomical localization and regulation by ovarian state. Biol Reprod 1993;49:
4316.
Karsch FJ, Dahl GE, Evans NP, Manning JM, Mayfield KP,
Moenter SM, et al. Seasonal changes in gonadotropin-reelasing
hormone secretion in the ewe: alteration in response to the
negative feedback action of estradiol. Biol Reprod 1999;49:
137783.
Nett TM, Turzillo AM, Baratta M, Rispoli LA. Pituitary effects
of steroid hormones on secretion of follicle-stimulating hormone and luteinizing hormone. Domest Anim Endocrinol
2002; 23:3342.
Barb CR. The brain-pituitary-adipocyte axis: role of leptin in
modulating neuroendocrine function. J Anim Sci 1999;77:
124957.
Dobson H, Smith RF. What is stress, and how does it affect
reproduction? Anim Reprod Sci 2000;6061:74352.
Wauters M, Considine RV, Van Graal LF. Human leptin: from
an adipocyte hormone to an endocrine mediator. Eur J Endocrinol 2000;143:293311.
Tilbrook AJ, Turner AI, Clarke IJ. Stress and reproduction:
central mechanisms and sex differences in non-rodent species.
Stress 2002;5:83100.
Barb CR, Barrett JB, Kraeling RR. Role of leptin in modulating
the hypothalamic-pituitary axis and luteinizing hormone secretion in the prepuberal gilt. Domest Anim Endocrinol 2004;26:
20114.

[61] Breen KM, Karsch FJ. Does cortisol inhibit pulsatile luteinizing
hormone secretion at the hypothalamic or pituitary level?
Endocrinology 2004;145:6928.
[62] Schneider F, Brussow KP, Kanitz E, Otten W, Tuchscherer A.
Maternal reproductive hormone levels after repeated ACTH
application to pregnant gilts. Anim Reprod Sci 2004;81:
31327.
[63] Chang WJ, Barb CR, Kraeling RR, Rampacek GB, Leshin LS.
Involvement of the central noradrenergic system in opioid
modulation of luteinizing hormone and prolactin secretion in
the pig. Biol Reprod 1993;49:17680.
[64] Herbison AE. Noradrenergic regulation of cyclic GnRH secretion. Rev Reprod 1997;2:116.
[65] Hoffman GE, Berghorn KA. Gonadotropin-releasing hormone
neurons: their structure and function. Sem Reprod Endocrinol
1997;15:517.
[66] Malpaux B, Thiery JC, Chemineau P. Melatonin and seasonal
control of reproduction. Reprod Nutr Dev 1999;39:35566.
[67] Ortmann O, Diedrich K. Pituitary and extrapituitary actions of
gonadotropin-releasing hormone and its analogues. Hum
Reprod Suppl 1999;1:194206.
[68] Ziecik AJ, Sienkiewicz W, Okrasa S, Kalamarz H, Lakomy M,
Kraeling RR. Concentration and distribution of neuropeptide Y,
galanin, b-endorphin, vasoactive intestinal peptide and gonadotropin-releasing hormone in the hypothalamus of gilts during
oestrogen-induced surge secretion of luteinizing hormone.
Reprod Dom Anim 1999;34:47787.
[69] Prunier A, Quesnel H. Nutritional influences on the hormonal
control of reproduction in female pigs. Livest Prod Sci 2000;
63:116.
[70] McCann SM, Kimura M, Karanth S, Yu W, Rettori V. Role
of nitric oxide in the neuroendocrine response to cytokines.
In: Gaillard RC, editor. Neuroendocrine-immune interactions, vol. 29. Basel: Karger. Front Horm Res; 2002. p.
11729.
[71] Evans JJ. Modulation of gonadotropin levels by peptides acting
at the anterior pituitary gland. Endocr Rev 1999;20:4667.
[72] Kaiser UB, Conn PM, Chin WW. Studies of gonadotropinreleasing hormone (GnRH) action using GnRH receptorexpressing pituitary cell lines. Endocr Rev 1997;18:4670.
[73] Dalkin AC, Burger LL, Aylor AW, Haisenleder DJ, Workman
LJ, Cho S, et al. Regulation of gonadotropin subunit gene
transcription by gonadotropin-releasing hormone: measurement of primary transcript ribonucleic acids by quantitative
reverse transcription-polymerase chain reaction assays. Endocrinology 2001;142:13946.
[74] Burger LL, Haisenleder DJ, Dalkin AC, Marshall JC. Regulation of gonadotropin subunit gene transcription. J Mol Endocrinol 2004;33:55984.
[75] De Koning J, Lambalk CB, Helmerhorst FM, Helder MN. Is
GnRH self-priming an obligatory feature of the reproductive
cycle? Hum Reprod 2001;16:20914.
[76] Caraty A, Antoine C, Delaleu B, Locatelli A, Bouchard P,
Gautron JP, et al. Nature and bioactivity of releasing-hormone
(GnRH) secreted during the GnRH surge. Endocrinology 1995;
136:345260.
[77] DOcchio MJ, Gifford DR, Earl CR, Weatherly T, von Rechenberg W. Pituitary and ovarian responses of post-partum acyclic
beef cows to continuous long-term GnRH and GnRH agonist
treatment. J Reprod Fert 1989;85:495502.
[78] DOcchio MJ, Fordyce G, Whyte TR, Jubb TF, Fitzpatrick LA,
Cooper NJ, et al. Use of GnRH agonist implants for long-term
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
705
suppression of fertility in extensively managed heifers and

cows. Anim Reprod Sci 2002;74:15162.
Gong JG, Campbell BK, Bramley TA, Gutierrez CG, Peters
AR, Webb R. Suppression in the secretion of follicle-stimulating hormone and luteinizing hormone, and ovarian follicle
development in heifers continuously infused with a gonadotropin-releasing hormone agonist. Biol Reprod 1996;55:6874.
Viczarra JA, Wettemann RP, Braden DT, Turzillo AM, Nett
TM. Effect of gonadotropin-releasing hormone (GnRH) pulse
frequency on serum and pituitary concentrations of luteinizing
hormone and follicle-stimulating hormone, GnRH receptors,
and messenger ribonucleic acid for gonadotropin subunits in
cows. Endocrinology 1997;138:594601.
Schneider F, Bellmann A, Becker F, Bambang Poernomo S,
Rehfeldt C, Nurnberg G, et al. Gonadotropin release in periovulatory heifers after GnRH analogs measured by two types
of immunoassays. Exp Clin Endocrinol Diabetes 2002;110:
23544.
Aspden WJ, Jackson A, Trigg TE, DOcchio MJ. Pituitary
expression of LHbeta- and FSHbeta-subunit mRNA, cellular
distribution of LHbeta-subunit mRNA and LH and FSH synthesis during and after treatment with a gonadotrophin-releasing
hormone agonist in heifers. Reprod Fertil Dev 2003;15:14956.
Padmanabhan V, McNeilly AS. Is there an FSH-releasing
factor? Reproduction 2001;121:2130.
Lumpkin MD, Moltz JH, Yu WH, Samson WK, McCann SM.
Purification of FSH-releasing factor: its dissimilarity from
LHRH of mammalian, avian and piscian origin. Brain Res
Bull 1987;18:1758.
Millar R, Lowe S, Conklin D, Pawson A, Maudsley S, Troskie
B, et al. A novel mammalian receptor for the evolutionarily
conserved type II GnRH. Proc Nat Acad Soc USA 2001;
98:963741.
Yu WH, Karanth S, Walczewska A, Sower SA, McCann SM. A
hypothalamic follicle stimulating hormone releasing decapeptide in the rat. Proc Natl Acad Sci USA 1997;94:9499503.
Dees WL, Dearth RK, Hooper RN, Brinsko SP, Romano JE,
Rahe H, et al. Lamprey gonadotropin-releasing hormone-III
selectively follicle stimulating hormone in the bovine. Domest
Anim Endocrinol 2001;20:27988.
Gault PM, Morgan K, Pawson AJ, Millar RP, Lincoln GA.
Sheep exhibit novel variations in the organization of the
mammalian type II gonadotropin-releasing hormone receptor
gene. Endocrinology 2004;145:236274.
Padmanabhan V, Brown MB, Dahl GE, Evans NP, Karsch FJ,
Mauger DT. Neuroendocrine control of follicle-stimulating
hormone (FSH) secretion: III. Is there a gonadotropin-releasing
hormone-independent component of episodic FSH secretion in
ovariectomized and luteal phase ewes? Endocrinology 2003;
144:138092.
Gharib SD, Wierman ME, Shupnik MA, Chin WW. Molecular
biology of the pituitary gonadotropins. Endocr Rev 1990; 11:
17799.
Rispoli LA, Nett TM. Pituitary gonadotropin-releasing hormone (GnRH) receptor: Structure, distribution and regulation
of expression. Anim Reprod Sci 2005;88:5774.
Nett TM, Cermak D, Braden T, Manns J, Niswender GD.
Receptors for GnRH and estradiol and pituitary content of
gonadotropins in beef cows. I. Changes during the estrous
cycle. Domest Anim Endocrinol 1987;4:12332.
Wu JC, Sealfon SC, Miller WL. Gonadal hormones and
gonadotropin-releasing-hormone (GnRH) alter messenger
706
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]

ribonucleic acid levels for GnRH receptors in sheep. Endocrinology 1994;134:184650.
Brooks J, McNeilly AS. Regulation of gonadotrophin-releasing
hormone receptor expression in the ewe. Anim Reprod Sci
1996;42:8998.
Turzillo AM, Nett TM. Regulation of GnRH receptor gene
expression in sheep and cattle. J Reprod Fertil Suppl 1999;
54:7586.
Cheng KW, Cheng CK, Leung PC. Differential role of PR-A
and PR-B isoforms in transcription regulation of human GnRH
receptor gene. Mol Endocrinol 2001;15:207892.
Reinhart J, Mertz LM, Catt KJ. Molecular cloning and expression of the rat pituitary gonadotropin-releasing hormone receptor. J Biol Chem 1992;267:212814.
Tsutsumi M, Zhou W, Millar RP, Mellon PL, Roberts JL,
Flanagan CA, et al. Cloning and functional expression of a
mouse gonadotropin-releasing hormone receptor. Mol Endocrinol 1992;6:11639.
Eidne KA, Sellar RE, Couper G, Anderson L, Taylor PL.
Molecular cloning and characterisation of the rat pituitary
gonadotropin-releasing hormone (GnRH) receptor. Mol Cell
Endocrinol 1992;90:R59.
Kaiser UB, Zhao D, Cardona GR, Chin WW. Isolation and
characterization of cDNAs encoding the rat pituitary gonadotropin-releasing hormone receptor. Biochem Biophys Res
Commun 1992;189:164552.
Brooks J, Taylor PL, Saunders PTK, Eidne KA, Struthers WJ,
McNeilly AS. Cloning and sequencing of the sheep pituitary
gonadotropin-releasing hormone receptor and changes in
expression of its mRNA during the estrous cycle. Mol Cell
Endocrinol 1993;94:R237.
Illing N, Jacobs GF, Becker II, Flanagan CA, Davidson JS,
Eales A, et al. Comparative sequence analysis and functional
characterization of the cloned sheep gonadotropin-releasinghormone receptor reveal differences in primary structure and
ligand specificity among mammalian receptors. Biochem Biophys Res Commun 1993;196:74551.
Chi L, Zhou W, Prikhozhan A, Flanagan C, Davidson JS,
Golembo M, et al. Cloning and characterization of the human
GnRH receptor. Mol Cell Endocr 1993;91:R16.
Kakar SS, Musgrove LC, Devor DC, Sellers JC, Neill JD.
Cloning, sequencing, and expression of human gonadotropin
releasing hormone (GnRH) receptor. Biochem Biophys Res
Commun 1992;30:28995.
Kakar SS, Rahe CH, Neill JD. Molecular cloning, sequencing,
and characterizing the bovine receptor for gonadotropin releasing hormone (GnRH). Domest Anim Endocrinol 1993;10:
33542.
Weesner GD, Matteri RL. Nucleotide sequence of luteinizing
hormone-releasing hormone (LHRH) receptor cDNA in the pig
pituitary (Rapid Communication). J Anim Sci 1994;72:1911.
Wess J. G-protein-coupled receptors: molecular mechanisms
involved in receptor activation and selectivity of G protein
recognition. FASEB J 1997;11:34654.
Ji TH, Grossmann M, Ji I. G-protein coupled receptors. I.
Diversity of receptor-ligand interactions. J Biol Chem 1998;
273:17299302.
Gether U. Uncovering molecular mechanisms involved in
activation of G protein coupled receptors. Endocr Rev 2000;
21:90113.
Naor Z, Millar RP, Seger R. Signaling of GnRH receptor in
pituitary gonadotrophs. In: GnRH analogs in human reproduc-
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
tionstate of the art 2005 Parthenon Publishing Group; 2005.

p. 113.
Haisenleder DJ, Yasin M, Dalkin AC, Gilrain C, Marshall JC.
GnRH regulates steroidogenic factor-1 (SF-1) gene expression
in the rat pituitary. Endocrinology 1996;137:571922.
Halvorson LM. Transcriptional regulation of the LH beta gene
by gonadotropin-releasing hormone and the protein kinase C
system. Vitam Horm 2000;60:195227.
Cheng KW, Leung PC. The expression, regulation and signal
transduction pathways of the mammalian gonadotropin-releasing hormone receptor. Can J Physiol Pharmacol 2000;78:1029
52.
McArdle CA, Franklin J, Green L, Hislop JN. Signalling,
cycling and desensitisation of gonadotrophin-releasing hormone receptors. J Endocr 2002;173:111.
Cheng CK, Leung PC. Molecular biology of gonadotropinreleasing hormone (GnRH)-I, GnRH-II, and their receptors in
humans. Endocr Rev 2005;26:283306.
Neill JD, Duck LW, Sellers JC, Musgrove LC. A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH
II in primates. Biochem Biophys Res Commun 2001;282:
10128.
Millar R, Conklin D, Lofton-Day C, Hutchinson E, Troskie B,
Illing N, et al. A novel human GnRH receptor homolog gene:
abundant and wide tissue distribution of the antisense transcript. J Endocrinol 1999;162:11726.
Flanagan CA, Millar RP, Illing N. Advances in understanding
gonadotrophin-releasing hormone receptor structure and
ligands interactions. Rev Reprod 1997;2:11320.
Wang L, Bogerd J, Choi HS, Seong JY, Soh JM, Chun SY, et al.
Three distinct types of GnRH receptor characterized in the
bullfrog. Proc Natl Acad Soc USA 2001;98:3616.
Bull P, Morales P, Huyser C, Socias T, Castellon EA. Expression of GnRH receptor in mouse and rat testicular germ cells.
Mol Hum Reprod 2000;6:5826.
Stojilkovic SS, Reinhart J, Catt KJ. Gonadotropin releasing
hormone receptors: structure and signal transduction pathways.
Endocr Rev 1994;15:46299.
Bauer-Dantoin AC, Jameson JL. Gonadotropin-releasing-hormone messenger ribonucleic acid expression in the ovary
during the rat estrous cycle. Endocrinology 1995;136:44328.
Kakar SS, Grizzle WE, Neill JD. The nucleotide sequences of
human GnRH receptors in breast and ovarian tumors are
identical with that found in pituitary. Endocrinology 1995;
106:1459.
Wolfahrt S, Kleine B, Jarry H, Rossmanith WG. Endogenous
regulation of the GnRH receptor by GnRH in the placenta. Mol
Hum Reprod 2001;7:8995.
Chou CS, Beristain AG, MacCalman CD, Leung PC. Cellular
localization of gonadotropin-releasing hormone (GnRH) I and
GnRH II in first-trimester human placenta and deciduas. J Clin
Endocrinol Metab 2004;89:145966.
Grundker C, Gunthert AR, Millar RP, Emons G. Expression of
gonadotropin-releasing hormone II (GnRH-II) receptor in
human endometrial and ovarian cancer cells and effect of
GnRH-II on tumor cell proliferation. J Clin Endocrinol Metab
2002;87:142730.
Enomoto M, Endo D, Kawashima S, Park MK. Human type II
GnRH receptor mediates effects of GnRH on cell proliferation.
Zool Sci 2004;21:76370.
Eicke N, Gunthert AR, Viereck V, Siebold D, Behe M, Becker
T, et al. GnRH-II receptor-like antigenicity in human placenta
[129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
[145]
[146]
and in cancers of human reproductive organs. Eur J Endocrinol

2005;153:60512.
Morgan K, Conklin D, Pawson AJ, Sellar R, Ott TR, Millar RP.
A transcriptionally active human type II gonadotropin-releasing hormone receptor gene homolog overlaps two genes in the
antisense orientation on chromosome 1q. 12. Endocrinology
2003;144:42336.
Neill JD, Musgrove LC, Duck LW. Newly recognized GnRH
receptors: function and relative role. Trends Endocrinol Metab
2004;15:38392.
Enomoto M, Park MK. GnRH as a cell proliferation regulator:
mechanism of action and evolutionary implications. Zool Sci
2004;21:100513.
Whitelaw PF, Eidne KA, Sellar R, Smyth CD, Hillier SG.
Gonadotropin-releasing hormone receptor messenger ribonucleic acid expression in rat ovary. Endocrinology 1995;136:
1729.
Canipari R. Oocyte-granulosa cell interactions. Hum Reprod
Update 2000;6:27989.
Jones SW. Chicken II luteinizing hormone-releasing hormone
inhibits the M-current of bullfrog sympathetic neurons. Neurosci Lett 1987;80:1804.
Igarashi M, McCann SM. A hypothalamic follicle stimulating
hormone releasing factor. Endocrinology 1964;79:44652.
Schally AV, Arimura A, Redding TW, Debeljuk L, Carter W,
DuPont A, et al. Re-examination of porcine and bovine
hypothalamic fractions for additional luteinizing and follicle
stimulating hormone-releasing activities. Endocrinology 1976;
98:38091.
Gault PM, Maudsley S, Lincoln GA. Evidence that gonadotropin-releasing hormone II is not a physiological regulator of
gonadotropin secretion in mammals. J Neuroendocrinol 2003;
15:8319.
McCann SM, Yu WH. FSH-releasing peptides. US Patent
6,300,471 (2001).
McCann SM, Karanth S, Mastronardi CA, Dees WL, Childs
G, Miller R, et al. Control of gonadotropin secretion by
follicle-stimulating hormone-releasing factor, luteinizing
hormone-releasing hormone, and leptin. Arch Med Res
2001;32:47685.
Kovacs M, Seprodi J, Koppan M, Horvath JE, Vincze B, Teplan
I, et al. Lamprey gonadotropin hormone-releasing hormone-III
has no selective follicle-stimulating hormone-releasing effect
in rats. J Neuroendocrinol 2002;14:64755.
Amstalden M, Zieba DA, Garcia MR, Stanko RL, Welsh Jr TH,
Hansel WH, et al. Evidence that lamprey GnRH-III does not
release FSH selectively in cattle. Reproduction 2004;127:
3543.
Heredi-Szabo K, Lubke J, Toth G, Murphy RF, Lovas S.
Importance of the central region of lamprey gonadotropinreleasing hormone III in the inhibition of breast cancer cell
growth. Peptides 2005;26:41922.
Kauffman AS, Rissman EF. The evolutionarily conserved
gonadotropin-releasing hormone II modifies food intake. Endocrinology 2004;145:68691.
Pell JM, Aston R. Principles of immunomodulation. Livestock
Prod Sci 1995;42:12333.
Thatcher WW, Drost M, Savio JD, Macmillan KL, Entwistle
KW, Schmitt EJ, et al. New clinical uses of GnRH and its
analogues in cattle. Anim Reprod Sci 1993;33:2749.
Peters AR. Veterinary clinical application of GnRHquestions
of efficacy. Anim Reprod Sci 2005;88:15567.
707
[147] Herbert CA, Trigg TE. Applications of GnRH in the control and
management of fertility in female animals. Anim Reprod Sci
2005;88:14153.
[148] Kittok RJ, Britt JH, Convey EM. Endocrine response after
GnRH in luteal phase cows and cows with follicular cysts. J
Anim Sci 1973;37:9859.
[149] Cantley TC, Garverick HA, Bierschwal CJ, Martin CE, Youngquist RS. Hormonal responses of dairy cows with ovarian cysts
to GnRH. J Anim Sci 1975;41:166673.
[150] Bartolome JA, Sozzi A, McHale J, Melendez P, Arteche ACM,
Silvestre FT, et al. Resynchronisation of ovulation and timed
insemination in lactating dairy cows, II. assigning protocols
according to stages of the estrous cycle, or presence of ovarian
cysts or anestrus. Theriogenology 2005;63:162842.
[151] Hyland JH, Wright PJ, Clarke IJ, Carson RS, Langsford DA,
Jeffcot LB. Infusion of gonadotrophin-releasing hormone
(GnRH) induces ovulation and fertile oestrus in mares during
seasonal anoestrus. J Reprod Fertil Suppl 1987;35:21122.
[152] Mumford EL, Squires EL, Jochle W, Harrison LA, Nett TM,
Trigg TE. Use of deslorelin short-term implants to induce
ovulation in cycling mares during three consecutive estrous
cycles. Anim Reprod Sci 1995;39:12940.
[153] Brussow KP, Jochle W, Huhn U. Control of ovulation with a
GnRH analog in gilts and sows. Theriogenology 1996;46:925
34.
[154] Chebel R, Santos JEP, Cerri RLA, Juchem S, Galvao KN,
Thatcher WW. Effect of resynchronization with GnRH on day
21 after artificial insemination on pregnancy rate and pregnancy
loss in lactating dairy cows. Theriogenology 2003;60:138999.
[155] Ambrose JD, Pires MF, Moreira F, Diaz T, Binelli M, Thatcher
WW. Influence of deslorelin (GnRH-agonist) implant on
plasma progesterone, first wave dominant follicle and pregnancy in dairy cattle. Theriogenology 1998;50:115770.
[156] Davis TL, Mussard ML, Jiminez-Severiano H, Enright WJ,
Kinder JE. Chronic treatment with an agonist of gonadotropinreleasing hormone enhances luteal function in cattle. Biol
Reprod 2003;69:398403.
[157] Hampton JH, Bader JF, Lamberson WR, Smith MF, Youngquist
RS, Garverick HA. Gonadotropin requirements for dominant
follicle selection in GnRH-agonist treated cows. Reproduction
2004;127:695703.
[158] Beck NFG, Peters AR, Williams SP. The effect of GnRH
analogue (buserelin) treatment on day 12 post mating on the
reproductive performance of ewes. Anim Prod 1994;58:2437.
[159] Peters AR, Martinez TA, Cook AJ. A meta-analysis of studies
of the effect of GnRH 11-4 days after insemination on pregnancy rates in cattle. Theriogenology 2000;54:131727.
[160] Newcombe JR, Martinez TA, Peters AR. The effect of the
gonadotropin-releasing hormone analog, buserelin, on pregnancy rates in horses and pony mares. Theriogenology 2001;
55:161931.
[161] Unger C, Schneider F, Hoppen HO, Becker F, Nurnberg G,
Kanitz W. Pregnancy rates in mares after application of gonadotropin releasing hormone analogue, Buserelin, in warmblood
mares. Theriogenology 2002;58:6358.
[162] Yavas Y, Walton JS. Induction of ovulation in post partum
suckled beef cows: a review. Theriogenology 2000;54:123.
[163] Schneider F, Rehbock F. Induction of fertile cycles in the
Blackhead sheep during the anoestrus period. Arch Anim Breed
2003;46:4761.
[164] Bartlewski PM, Aravindakshan J, Beard AP, Nelson ML,
Batiasta-Arteaga S, Cook J, et al. Effects of medroxyproges-
708
[165]
[166]
[167]
[168]
[169]
[170]
[171]
[172]
[173]
[174]
[175]
[176]
[177]

terone acetate (MAP) on ovarian antral follicle development,
gonadotrophin secretion and response to ovulation induction
with gonadotrophin-releasing hormone (GnRH) in seasonally
anoestrous ewes. Anim Reprod Sci 2004;81:6375.
Burke JM, De La Sota RL, Risco CA, Staples CR, Schmitt EJP,
Thatcher WW. Evaluation of timed insemination using a gonadotropin-releasing hormone agonist in lactating dairy cows. J
Dairy Sci 1996;79:138593.
Stevenson JS, Kobayashi Y, Thompson KE. Reproductive
performance of dairy cows in various programmed breeding
systems including Ovsynch and combinations of gonadotropinreleasing hormone and prostaglandin F2. J Dairy Sci 1999;99:
50615.
Bartolome JA, Silvestre FT, Kamimura S, Arteche ACM,
Melendez P, Kelbert D, et al. Resynchronisation of ovulation
and timed insemination in lactating dairy cows, I. use of the
Ovsynch and Heatsynch protocols after non-pregnancy diagnosis by ultrasonography. Theriogenology 2005;63:161727.
Deligiannis C, Valasi I, Rekkas CA, Goulas P, Theodosiadou E,
Lainas T, et al. Synchronization of ovulation and fixed time
intrauterine insemination in ewes. Reprod Domest Anim 2005;
40:610.
Pursley JR, Mee MO, Wiltbank MC. Synchronization of ovulation in dairy cows using PGF2a and GnRH. Theriogenology
1995;44:91523.
Twagiramungu H, Guilbault LA, Dufour JJ. Synchronization of
ovarian follicular waves with a gonadotropin-releasing hormone agonist to increase the precision of estrus in cattle: a
review. J Anim Sci 1995;73:314151.
Gong JG, Bramley TA, Gutierrez CG, Peters AR, Webb R.
Effects of chronic treatment with gonadotrophin-releasing
hormone agonist on peripheral concentrations of FSH and
LH, and ovarian function in heifers. J Reprod Fertil 1995;
105:26370.
Maclellan LJ, Bergfeld EGM, Earl CR, Fitzpatrick LA, Aspden
WJ, Kinder JE, et al. Influence of the luteinizing hormonereleasing hormone agonist, deslorelin, on patterns of estradiol17b and luteinizing hormone secretion, ovarian follicular
responses to superstimulation with follicle-stimulating hormone, and recovery and in vitro development of oocytes in
heifer calves. Biol Reprod 1997;56:87884.
Rajamahendran R, Ambrose JD, Schmitt EJ, Thatcher MJ,
Thatcher WW. Effects of buserelin injection and deslorelin
(GnRH-agonist) implants on plasma progesterone, LH, accessory CL formation, follicle and corpus luteum dynamics in
Holstein cows. Theriogenology 1998;50:114155.
DOcchio MJ, Fordyce G, Whyte TR, Aspden WJ, Trigg TE.
Reproductive responses of cattle to GnRH agonists. Anim
Reprod Sci 2000;6061:43342.
Schneider F, Heleil B, Alm H, Torner H, Becker F, Viergutz T,
et al. Endocrine, morphological, and cytological effects of a
depot GnRH agonist in bovine. Anim Reprod Sci 2006;92:
928.
Adams TE. Using gonadotropin-releasing hormone (GnRH)
and GnRH analogs to modulate testis function and enhance the
productivity of domestic animals. Anim Reprod Sci 2005;
88:12739.
Xue JL, Dial GD, Bartsh S, Kerkeart B, Squires EJ, Marsh WE,
et al. Influence of a gonadotropin-releasing hormone agonist on
circulating concentrations of luteinizing hormone and testosterone and tissue concentrations of compounds associated with
boar taint. J Anim Sci 1994;72:12908.
[178] Schneider F, Falkenberg H, Kuhn G, Nurnberg K, Rehfeldt C,

Kanitz W. Effects of treating young boars with a GnRH depot
formulation on endocrine functions, testis size, boar taint,
carcass composition and muscular structure. Anim Reprod
Sci 1998;50:6980.
[179] Magdwick S, Evans ACO, Beard AP. Treating heifers with
GnRH from 4 to 8 weeks of age advanced growth and the age at
puberty. Theriogenology 2005;63:232333.
[180] Esbenshade KL, Britt JH. Active immunization of gilts against
gonadotropin-releasing hormone: effects on secretion of gonadotropins. reproductive function, and responses to agonists of
gonadotropin-releasing hormone. Biol Reprod 1985;33:
56977.
[181] Prendiville DJ, Enright WJ, Crowe MA, Finnerty M, Roche JF.
Normal or induced secretory patterns of luteinising hormone
and follicle-stimulating hormone in anoestrous gonadotrophinreleasing hormone-immunised and cyclic control heifers. Anim
Reprod Sci 1996;45:17790.
[182] Stevens JD, Sosa JM, DeAvila DM, Oatley JM, Bertrand KP,
Gaskins CT, et al. Luteinizing-hormone-releasing hormone
fusion protein vaccines block estrous cycle activity in beef
heifers. J Anim Sci 2005;83:1529.
[183] Brown BW, Mattner PE, Carroll PA, Hoskinson RM, Rigby
RDG. Immunization of sheep against GnRH early in life:
effects on reproductive function and hormones in ewes. J
Reprod Fertil 1995;103:1315.
[184] Mariana JC, Monniaux D, Craty A, Pisselet C, Fontaine J,
Solari A. Immunization of sheep against GnRH early in life:
effects on gonadotropins, follicular growth and responsiveness
of granulosa cells to FSH and IGF-I in two breeds of sheep with
different prolificacy (Romanov and Ile-de-France). Domest
Anim Endocrinol 1998;15:195207.
[185] Tast A, Love RJ, Clarke W, Evans G. Effects of active and
passive gonadotropin-releasing hormone immunization on
recognition and establishment of pregnancy in pigs. Reprod
Fertil Dev 2000;12:27782.
[186] Driancourt MA, Locatelli A, Prunier A. Effects of gonadotrophin deprivation on follicular growth in gilts. Reprod Nutr Dev
1995;35:66373.
[187] Dobson H, Campbell BK, Scaramuzzi RJ. Use of a GnRH
antagonist in conjunction with low amplitude, high frequency
LH pulses to induce follicular growth without an LH surge and
ovulation. Anim Reprod Sci 1997;46:21322.
[188] Fike KE, Bergfeld EG, Cupp AS, Kojima FN, Mariscal V,
Sanchez T, et al. Gonadotropin secretion and ovarian follicles
during oestrous cycles in heifers treated with luteinizing hormone releasing hormone antagonist. Anim Reprod Sci 1997;
49:83100.
[189] Patterson-Day DJ, Geisert RD, Hill CM, Minton JE, McCann
JP, Morgan GL. GnRH antagonist inhibition of luteinizing
hormone secretion and ovulation in the pig. Anim Reprod
Sci 1997;49:20714.
[190] Oussaid B, Mariana JC, Poulin N, Fontaine J, Lonergan P,
Beckers JF, et al. Reduction of the developmental competence
of sheep oocytes by inhibition of LH pulses during the follicular
phase with a GnRH antagonist. J Reprod Fertil 1999;117:717.
[191] Brussow KP, Schneider F, Nurnberg G. Alteration of gonadotrophin and steroid hormone release, and ovarian function
by a GnRH antagonist in gilts. Anim Reprod Sci 2001;66:
11728.
[192] Gautron JP, Gras C, Enjalbert A. Molecular polymorphism of
native gonadotropin-releasing hormone (GnRH) is restricted to

mammalian GnRH and [hydroxyproline] GnRH in the developing rat brain. Neuroendocrinology 2005;81:6986.
[193] Kauffold J, Schneider F, Zaremba W, Brussow KP. Lamprey
GnRH-III (l-GnRH-III) selectively elicits FSH response after
administration to barrows. Reprod Domest Anim 2005;40:
4759.
[194] Porter MB, Cleaver BD, Peltier M, Robinson G, Thatcher WW,
Sharp DC. Comparative study between pony mares and
ewes evaluating gonadotrophic response to administration of
709
gonadotrophin-releasing hormone. J Reprod Fertil 1997;110:

21929.
[195] Khosravi S, Leung PC. Differential regulation of gonadotropinreleasing hormone (GnRH)I and GnRHII messenger ribonucleic acid by gonadal steroids in human granulosa luteal cells. J
Clin Endocrinol Metab 2003;88:66372.
[196] Siler-Khodr TM, Yu FQ, Wei P, Tao SX, Liu YX. Contraceptive
action of a gonadotropin-releasing hormone II analog in the
rhesus monkey. J Clin Endocrinol Metab 2004;89:451320.

Jurnal GNRH 3

Încărcat de

Informații document

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Jurnal GNRH 3

Încărcat de

Drepturi de autor:

Formate disponibile

Theriogenology 66 (2006) 691709

Gonadotropin-releasing hormone (GnRH) and its natural

Introduction to gonadotropin-releasing hormone . . . . . . . . . .

F. Schneider et al. / Theriogenology 66 (2006) 691709

Hypophyseal and extrahypophyseal effects of natural GnRHs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

modulatory functions [13,17]. The neuroendocrine axis

F. Schneider et al. / Theriogenology 66 (2006) 691709

consequently co-secreted with GnRH [10,25] may be

Apart from GnRH-I and, very often, GnRH-II

F. Schneider et al. / Theriogenology 66 (2006) 691709

The most ancient GnRH form is thought to be oGnRH

3. Release mechanisms of GnRH-I

F. Schneider et al. / Theriogenology 66 (2006) 691709

Peptide is released from a cell within the pituitary, e.g.

F. Schneider et al. / Theriogenology 66 (2006) 691709

by a single neuroendocrine factor seems to be contradictory. High-frequency GnRH pulses favour LH

itself and E2. Developing ovarian follicles produce

F. Schneider et al. / Theriogenology 66 (2006) 691709

increase in cAMP and an activation of members of the

GnRH-II than GnRH-I [30,119]. Type-II receptors are

F. Schneider et al. / Theriogenology 66 (2006) 691709

properties, e.g. in terms of stimulating the IP3 production

For a few decades, hypothalamic GnRH-I has been

F. Schneider et al. / Theriogenology 66 (2006) 691709

Central and peripheral

Regulation of endocrine functions

Tumors of the female

Inhibition of cell proliferation

Adapted to Limonta et al. [8].

F. Schneider et al. / Theriogenology 66 (2006) 691709

reproduction are closely linked, it may be plausible that

F. Schneider et al. / Theriogenology 66 (2006) 691709

agonists and their blocking effects are immediate but

In cattle but also in other species numerous

F. Schneider et al. / Theriogenology 66 (2006) 691709

Recently [147] it was reviewed that agonists when

regulation of the pituitary during IVF treatment regimes

F. Schneider et al. / Theriogenology 66 (2006) 691709

[9]. An inclusion of GnRHs in treatment schedules of

of tumor growth and progression in humans. Front Neuroendocrinol 2003;24:27995.

F. Schneider et al. / Theriogenology 66 (2006) 691709

[28] Wirsig-Wiechmann CR. Function of gonadotropin-releasing

in the tree shrew: first evidence for mesencephalic GnRH

F. Schneider et al. / Theriogenology 66 (2006) 691709

suppression of fertility in extensively managed heifers and

F. Schneider et al. / Theriogenology 66 (2006) 691709

tionstate of the art 2005 Parthenon Publishing Group; 2005.

F. Schneider et al. / Theriogenology 66 (2006) 691709

and in cancers of human reproductive organs. Eur J Endocrinol

F. Schneider et al. / Theriogenology 66 (2006) 691709

[178] Schneider F, Falkenberg H, Kuhn G, Nurnberg K, Rehfeldt C,

F. Schneider et al. / Theriogenology 66 (2006) 691709

gonadotrophin-releasing hormone. J Reprod Fertil 1997;110:

S-ar putea să vă placă și