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modify the GnRH response to hKP-10 nor peptide 234, it completely eliminated
both the hKP-10-induced stimulation and peptide 234-induced GnRH suppression
of GnRH release in pubertal monkeys ([
58
], also Guerriero and Terasawa, unpub-
lished observation). Moreover, replacement of E
2
in OVX pubertal monkeys only
partially restored the hKP-10-induced GnRH release that was absent in OVX puber-
tal monkeys [
58
]. These observations suggest that while, in prepubertal monkeys,
the response of KISS1R on GnRH neurons is independent of E
2
, in pubertal mon-
keys, functional changes in KISS1R occur as a consequence of the exposure to
increased circulating E
2
after puberty onset, such that KISS1R responsiveness is
enhanced by E
2
. Collectively, once the pubertal increase in E
2
occurs in the female
monkey, as a consequence of pubertal activation of the GnRH pulse generating
mechanism, the presence of E
2
appears to enhance the response of GnRH neurons
to kisspeptin [
58
]. Although to date, developmental changes in
KISS1R
mRNA in
ovariectomized monkeys have not been examined, it will be important to address
this issue further.
Kisspeptin Signaling and GnRH Pulse Generation
The hypothesis that kisspeptin neurons are a part of the neurocircuitry underlying
the GnRH pulse generating mechanism has been proposed by Goodman and col-
leagues, Maeda and colleagues, and Steiner and colleagues [
69
,
70
] (see also Chap.
14
)
. It is posited that pulsatility originates in ARC kisspeptin neurons containing
neurokinin B and dynorphin (called KNDy neurons) by reciprocal interactions of
neurokinin B (stimulatory) and dynorphin (inhibitory), and that an intermittent
output to the GnRH neuronal network is mediated by kisspeptin. This hypothesis
is based on several observations. First, periodic increases in multiunit activity
obtained from electrodes in the MBH are associated with LH pulses in several spe-
cies [
71
,
72
], and specifi cally in the ARC, as shown in the goat [
73
]. Second, the
neurokinin B receptor agonist, senktide, is a potent stimulator of ARC kisspeptin
neurons (presumably KNDy neurons) in the mouse [
74
], and the site of the stimu-
latory action of neurokinin B on GnRH-dependent LH release in the monkey
appears to be upstream of kisspeptin [
75
]. Third, in pubertal monkeys, pulses of
kisspeptin-54 released in the ARC-ME correlate to GnRH pulses 75% of the time
[
65
]. Fourth, repetitive iv injections of hKP-10 induce trains of GnRH-dependent
LH pulses in juvenile male monkeys, in which endogenous GnRH pulsatility is
minimal [
59
], presumably by activating KISS1R on GnRH terminals in the ME, as
kisspeptin and GnRH fi bers are found in extensive and intimate association in the
ME (Fig.
12.2
) [
76
]. Fifth, intra-ARC, not intra-POA, administration of the kiss-
peptin antagonist, peptide 234, profoundly suppressed LH pulse frequency [
77
],
although again the site of action of the antagonist is likely to be at the ME, as
recent electrophysiological studies by Alreja and Steiner indicate that kisspeptin is
unable to stimulate KNDy neurons in the mouse (see Chap.
16
). The contemporary
notion regarding the integral role played by KNDy neurons in GnRH pulse generation
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