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Fig. 8.12
Peptide 234 inhibits LH secretion and pulsatility. (
a
) Concentrations of LH are shown
in an oestrogen-replaced ovariectomised ewe treated with peptide 234 (
black bar, left
) or control
(
grey bar
,
right
). Arrows indicate LH pulses. Analysis revealed a signifi cant reduction in the mean
LH concentration and pulse amplitude after peptide 234 infusion. (
b
) Representative examples
illustrating the effects of intra-ARC injection of 500 nL aCSF (
left hand
; 3 injections at 30 min
intervals) or 50 pmol peptide 234 (
right hand
; 3 injections at 30 min intervals) in ovariectomised
17
-estradiol-replaced rats (
n
= 5-6).
Arrows
represent intra-ARC injections. (From Roseweir,
A.K., et al., Discovery of potent kisspeptin antagonists delineate physiological mechanisms of
gonadotropin regulation. J Neurosci. 2009. 29(12):3920-9, with permission from The Society for
Neuroscience and from Li, X.F., et al., Kisspeptin signalling in the hypothalamic arcuate nucleus
regulates GnRH pulse generator frequency in the rat. PLoS One. 2009. 4(12):e8334. Open Access)
β
samples. GnRH pulses were restored when the antagonist infusion was terminated.
This provides the fi rst direct evidence that KP is required for GnRH secretion and is
responsible for GnRH pulses at puberty [
26
]. Importantly, the antagonist did not
affect basal GnRH levels. Peptide 234 also suppressed GnRH pulses in another
study on pre-pubertal female rhesus monkeys during a 30 min infusion, and the
suppression continued for 90 min post-infusion (Fig.
8.11d
) [
28
], which may refl ect
lower levels of KP in pre-pubertal animals or differences in pharmacokinetics.
The role of KP in GnRH pulsatility was also investigated indirectly in ovariect-
omised ewes by monitoring peptide 234 effects on LH pulses when the antagonist
was infused i.c.v. as a 40
g over the ensuing hour. Peptide
234 reduced both LH pulse amplitude and pulse frequency during infusion, and this
inhibition continued for 2 h after termination of infusion (Fig.
8.12a
) [
26
]. Since a
reduction in pulse amplitude reduces the ability to detect pulses, the effects on pulse
frequency are uncertain. However, a reduction in LH pulse frequency is clearly
μ
g bolus followed by 40
μ
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