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leads to higher mean levels of the peptide in the S-ME of pubertal animals, which
is parallel to those seen in GnRH release during the course of puberty in female
monkeys [
67
,
68
].
As discussed in the previous section, developmental changes in GnRH release in
the rhesus monkey are independent of circulating gonadal steroids. Similar to ovar-
ian intact females [
67
], developmental increases in the pulse frequency and pulse
amplitude of GnRH release do not occur until the age of puberty in ovariectomized
monkeys [
68
]. Likewise, the pulse frequency and pulse amplitude of kisspeptin-54
release in ovariectomized monkeys do not increase until the age that puberty would
have been anticipated had the animals remained intact (Fig.
12.1
) [
66
]. Importantly,
the IPI of kisspeptin-54 release in ovarian intact and ovariectomized females at the
prepubertal stage is ~80 min, which is very similar to that of GnRH release [
67
,
68
],
whereas the IPI of kisspeptin-54 release at the pubertal stage is ~50 min, regardless
of the presence or absence of the ovary, which is, again, similar to the IPI of GnRH
release in animals at the same developmental stage (Fig.
12.1
) [
67
,
68
]. (The role of
kisspeptin in GnRH pulse generation will be further discussed in a later section.)
An impact of the ovary on kisspeptin-54 release is only observed in the pubertal
monkey, where both the pulse amplitude and mean release of kisspeptin-54 is mark-
edly increased by ovariectomy, presumably due to loss of negative feedback from
the ovarian steroid E
2
(Fig.
12.1
). In fact, administration of E
2
can suppress kiss-
peptin-54 release in pubertal monkeys, whereas kisspeptin-54 release in prepubertal
monkeys is insensitive to E
2
[
66
]. This developmental change in ovarian steroid
regulation of kisspeptin-54 release is similar to that seen with GnRH release [
27
].
Collectively, these observations indicate that the pubertal increase in kisspeptin-54
release occurs independently from an ovarian steroid hormone feedback mecha-
nism. Rather, the pubertal increase in pulsatile release of kisspeptin-54 in female
rhesus monkeys (and presumably male primates) requires a developmental change
in an upstream neuronal signal to the kisspeptin neuronal network.
Because developmental changes in KISS1R may also contribute to the pubertal
increase in GnRH release, in a second series of studies, Terasawa and colleagues
examined the developmental changes in GnRH release in response to the kisspeptin
agonist, hKP-10, and antagonist, peptide 234, administered directly into the S-ME.
While the GnRH response to hKP-10 is dose dependent in both ovarian intact pre-
pubertal and pubertal monkeys, a smaller response to a 10 nM dose of hKP-10 is
consistently observed in prepubertal monkeys as compared to pubertal monkeys
[
58
]. Release of GnRH in both prepubertal and pubertal monkeys is also suppressed
by peptide 234. These results suggest that the pubertal increase in pulsatile GnRH
release is, in part, due to an increased responsiveness of KISS1R in GnRH neurons
during the progression of puberty. This view is consistent with studies in transgenic
mice expressing GFP in GnRH neurons, in which electrical fi ring activity of GnRH
neurons stimulated by KP-10 increases across male puberty [
37
].
To further determine whether the enhanced responses of GnRH neurons to hKP-
10 in pubertal monkeys are due to higher levels of circulating E
2
at puberty, a similar
experiment examining the GnRH responsiveness to hKP-10 in ovariectomized
monkeys was conducted. While ovariectomy in prepubertal monkeys did not
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