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Jurnal GNRH 3
Jurnal GNRH 3
Jurnal GNRH 3
www.journals.elsevierhealth.com/periodicals/the
Review
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.
* 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
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692
692
694
696
692
5.
6.
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
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].
693
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
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
696
697
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].
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
Neuromodulation
Control of gonadotropin secretion
Stimulation of reproductive behavior
Placenta
Endometrium
Breast
Ovary
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
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
701
702
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
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