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FSH was not signifi cantly increased following IP kisspeptin-10 administration at
these doses [
4
]. Although gonadotropin levels were not increased at 60 min
post-injection, testosterone levels were signifi cantly elevated at this time, and a
larger 300 nmol dose of IP kisspeptin-10 signifi cantly increased both LH and FSH
levels at 60 min post-injection [
4
]. Navarro et al. found that an IP injection of
7.5 nmol of kisspeptin-10 signifi cantly increased plasma LH levels to a similar
extent as central administration of 1 nmol kisspeptin-10 at 15 min post-injection in
male Wistar rats [
5
]. However, the decay in plasma LH levels following IP kiss-
peptin-10 was more rapid when compared with ICV kisspeptin-10. Therefore, the
rapid onset of action of and subsequent rapid decay in LH levels following IP kiss-
peptin-10 may explain why Thompson et al. [
4
] were unable to detect an effect on
gonadotropin secretion at 60 min post-injection with the lower doses employed.
Hence, kisspeptin is capable of robustly stimulating gonadotropin secretion in a
number of species, including when given peripherally.
The Effect of Repeated Administration of Kisspeptin
on Gonadotropin Secretion
The effects of acute kisspeptin treatment on gonadotropin secretion are relatively
short-lived (several hours at most). It is therefore important, from a therapeutic per-
spective, to ascertain whether kisspeptin is able to stimulate gonadotropin release in
chronic dosing regimens.
Four IP injections of 1 nmol of mouse kisspeptin-(105-119) at 30-min intervals
in 2-4-month-old male mice resulted in a ~5-fold increase in plasma gonadotropin
levels measured 30 min after the last injection [
14
]. Likewise, four IP injections of
1 nmol kisspeptin-10 every 30 min to adult ovary-intact female Siberian hamsters
housed in a summer (breeding) photoperiod signifi cantly increased LH levels at
30 min after the last injection [
15
]. Hence, repeated IP administration of kisspeptin
is effective in stimulating gonadotropin secretion when given at 30 min intervals in
mice and hamsters. In addition, four IV boluses of 30 nmol/kg kisspeptin-10, via
intracardiac cannulae, to mobile male rats at 75 min intervals elicited LH secretory
bursts comparable to a single administration experiment (Table
4.2
) [
8
].
The effects of repetitive hourly kisspeptin administration were studied in pri-
mates and in ewes. Hourly IV pulses of 2
g (1.54 nmol) of kisspeptin-10 for 48 h
to GnRH-primed juvenile agonadal male Rhesus monkeys (a model considered to
be analogous to a peri-pubertal state in humans) stimulated a pulsatile pattern of
LH secretory pulses, similar in magnitude to those elicited by GnRH priming [
16
].
This kisspeptin-induced LH response was maintained for 48 h, and FSH secretion
was qualitatively similar to that of LH, although FSH pulses were less well-defi ned
[
16
]. In pre-pubertal ewe lambs (28 weeks of age) treated with hourly IV boluses
of kisspeptin at 20
µ
g (15.4 nmol) for 24 h, plasma LH levels were elevated within
15 min of the fi rst injection, as were the frequency and amplitude of LH pulses.
Four of six kisspeptin-treated lambs had LH surges 17 h after the start of the hourly
µ
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