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kisspeptin therapy; however, kisspeptin therapy did not accelerate the onset of
puberty in the lambs when compared with placebo [ 17 ]. Hence, hourly IV pulses
of kisspeptin were effective in stimulating LH secretion for as long as 48 h in pri-
mates and at least 24 h in ewes. This hourly administration regime may most accu-
rately refl ect the inter-pulse interval of endogenous kisspeptin secretion [ 18 ].
Using microdialysis, kisspeptin immunoreactivity (IR) was measured within the
stalk median eminence of female Rhesus monkeys. Kisspeptin IR had a pulsatile
pattern of secretion, with an inter-pulse interval of ~60 min, and 75% of kisspeptin
pulses corresponded to GnRH pulses [ 18 ]. Furthermore, kisspeptin-10 infusion
into the stalk median eminence stimulates GnRH release in a dose-dependent
manner [ 18 ]. This data suggests that pulsatile kisspeptin secretion stimulates pul-
satile release of GnRH, causing subsequent pulsatile gonadotropin secretion from
the pituitary gland.
Repeated IV administration of kisspeptin was also studied in ungulates. Adult
female goats in the luteal phase were given three injections of human kisspeptin-10
or GnRH at 5
g/kg (4.23 nmol/kg) at 2 h intervals. Plasma LH levels were increased
from baseline (0.41-0.56 ng/mL) to maximum values of 5.56 ng/mL, 10.72 ng/mL
and 7.72 ng/mL for each injection, respectively [ 10 ]. Plasma FSH levels increased
in a similar time-frame from a baseline of 0.62-0.78 ng/mL to peaks of 1.16 ng/mL,
2.02 ng/mL, and 1.60 ng/mL after the fi rst, second, and third kisspeptin-10 injec-
tion, respectively. GnRH elevated gonadotropins more gradually, but to a greater
maximum (LH: 34.99 ng/mL; FSH: 3.32 ng/mL) 30 min after the second injection
[ 10 ]. Hence, kisspeptin was able to stimulate gonadotropin secretion when admin-
istered peripherally at 2 h intervals, although to a lesser extent when compared with
GnRH.
Repeated ICV administration of 1 nmol of mouse kisspeptin-10 every 12 h to
pre-pubertal (day 26) female Wistar rats for 5 days increased LH levels tenfold.
While absent in all of the controls, 74% of repeatedly kisspeptin-treated immature
rats showed physical evidence of puberty [ 18 ]. Hence, repetitive ICV kisspeptin
administration was effective in inducing sexual maturation in juvenile female rats.
Furthermore, repeated central administration of kisspeptin-10 (1 nmol every 12 h
for 1 week) to under-nourished (30% restriction in food intake) pre-pubertal
(day 30) female rats induced physical markers of puberty in 60% of kisspeptin-
treated animals vs. none in the control group, along with elevated serum LH and
FSH levels [ 19 ].
Collectively, repeated kisspeptin administration in mice, rats, hamsters, and
goats was effective in stimulating gonadotropin levels (Table 4.2 ). Furthermore,
repeated administration of kisspeptin in immature rats was able to induce pubertal
maturation (although not in ewe lambs) with the dosing regimen employed.
These data suggest that kisspeptin could be used therapeutically to increase
gonadotropin and sex hormone levels, although it is not known whether kiss-
peptin would offer any therapeutic advantage over existing therapies for repro-
ductive disorders.
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