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change in the pituitary sensitivity to GnRH. It is well known that pituitary sensitiv-
ity to GnRH is infl uenced by levels of circulating sex steroids [
63
] and activity of
GnRH neurons also changes during different stages of the female menstrual cycle.
Likewise, levels of kisspeptin expression also change during the menstrual cycle
and after experimental sex steroid manipulations, such as gonadectomy [
64
].
Further work is needed to determine the precise extent to which differences in
kisspeptin sensitivity are consequences of differential hypothalamic (GnRH) vs.
pituitary sensitivity.
Conclusions
Kisspeptin has been shown to induce gonadotropin secretion in all non-human
mammalian species studied, and the effects are mediated via GnRH release.
However, it is important to note that endogenous secretion of kisspeptin is likely to
be pulsatile (~60 min inter-pulse interval) [
18
] and in much smaller quantities than
the pharmacological dosing strategies employed during the studies described in this
chapter.
Although most GnRH neurons have kisspeptin receptors, the ability of periph-
eral kisspeptin to stimulate gonadotropin release is striking, given that kisspeptin is
unlikely to be able to cross the blood-brain barrier. Peripherally circulating kiss-
peptin may interact with GnRH neurons at the OVLT and at the median eminence
to cause GnRH release [
34
,
65
]. Another possibility is that kisspeptin may act
through intermediary neurons, such as inhibitory GABA neurons located in circum-
ventricular regions of the brain, to modulate GnRH neuronal activity [
66
]. The abil-
ity of kisspeptin to stimulate GnRH release, even when administered peripherally,
is important for ease of administration in the development of therapeutic kisspeptin
regimens in the future. Further lessons from animal studies include the fi nding that
continuous exposure may result in tachyphylaxis to the effects of kisspeptin. This is
an important consideration for any translational usage of kisspeptin during chronic
dosing regimens.
There are only a small number of studies which directly compare the effects of
different kisspeptin isoforms on gonadotropin release. There are many more studies
utilizing kisspeptin-10 than longer isoforms, partly due to the greater availability
and easier synthesis of the former. In the in vivo situation, the effects of kisspeptin
are not only infl uenced by dosing regimens, kisspeptin isoforms, and species, but
also by nutritional status, age, stage of estrus cycle, and underlying hormonal milieu.
It can therefore be diffi cult to compare fi ndings between various kisspeptin studies,
with occasional non-congruent results being observed. However, intriguing differ-
ences in the effects of kisspeptin administration between individual mammalian
species may reveal important differences in reproductive physiology, which require
further investigation.
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