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100 pmol, over 5 min resulted in a dose-dependent increase in plasma LH levels that
lasted ~1 h [
35
]. Three bolus injections of peptide 234, a kisspeptin antagonist,
administered at 30-min intervals into the ARC reduced LH pulse frequency
(although not amplitude of LH pulses), suggesting that the ARC plays an important
role in the modulation of GnRH pulse frequency by kisspeptin [
35
].
In the male Rhesus monkey, kisspeptin-immunoreactive cells have been identi-
fi ed in the ARC, but not in the AVPV [
36
]. Alternatively, female Rhesus monkeys
have population of
Kiss1
mRNA expressing neurons in the ARC and the POA
(potentially a homologous region to the rodent AVPV) [
37
]. In the ARC, there are
only infrequent contacts made between GnRH neurons and kisspeptin neurons.
However, at the median eminence, kisspeptin and GnRH axons are extensively and
intimately associated, allowing for potential non-synaptic interaction between these
two groups of neurons [
36
]. Kisspeptin-54 release in the stalk median eminence of
monkeys is pulsatile, and ~75% of kisspeptin-54 pulses are correlated with GnRH
pulses [
18
]. Microdialysis infusion of 10 or 100 nM human kisspeptin-10 into the
medial basal hypothalamus (MBH; which includes the ARC) and the stalk median
eminence for 20 min stimulated GnRH release in a dose-dependent manner in both
pre-pubertal (low estradiol) and pubertal (elevated estradiol) ovarian-intact female
monkeys. Conversely, infusion of peptide 234, a kisspeptin antagonist, suppressed
GnRH release. Interestingly, the stimulation of GnRH release by kisspeptin-10 was
absent in ovariectomized post-pubertal, but not pre-pubertal, monkeys; this kiss-
peptin stimulation of GnRH could be partially restored in post-pubertal monkeys by
estradiol replacement. This suggests an important permissive role for estradiol in
the neural action of kisspeptin in monkeys, which is apparent only after puberty has
occurred; there may be a switch from estradiol-independent to estradiol-dependent
kisspeptin signaling within the hypothalamus after puberty [
38
].
Kisspeptin Actions in the Pituitary
While the predominant effect of kisspeptin is via the hypothalamus, likely via stim-
ulation of GnRH neurons, it has also been enquired whether kisspeptin may also
have an additional effect via the pituitary gland. In primary pituitary cell cultures
prepared from adult cyclic female baboons (
Papio anubis
), kisspeptin-10 (10
−14
to
10
−6
M) can dose-dependently stimulate LH release. Interestingly, estradiol
enhanced the relative LH response to kisspeptin-10, both alone and in combination
with GnRH [
39
]. However, while incubation of rat hypothalamic explants with
kisspeptin-10 stimulated the release of GnRH at a dose of 10 nM, kisspeptin doses
of up to 1,000 nM had no effect on the release of LH or FSH from rat pituitary cul-
tures in vitro [
4
]. In another study, incubation of pituitary cultures from peri-pubertal
male rats with kisspeptin-10 induced a rise in free cytosolic Ca
2+
concentration in
only 10% of rat pituitary cells [
40
]. Moreover, another study in rats found that incu-
bation of cultured male or female pituitary cells with kisspeptin-54 did not result in
in vitro gonadotropin release, even when primed with estradiol [
1
]. However,
Navarro et al. [
5
] incubated rat pituitary cultures in kisspeptin-10 and reported that
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