The Effects of Kisspeptin on Gonadotropin Release in Non-human Mammals - Kisspeptin Signaling in Reproductive Biology - page 70

6 h, ~2-fold at 12 h, and back to baseline by 24 h. Hence, desensitization to the
effects of continuous kisspeptin-54 occurs rapidly, commencing within just 12 h [ 2 ].
On the contrary, Roa et al. examined whether nutritional status infl uences the
effect of chronic kisspeptin-10 treatment in rodents. Kisspeptin-10, when admin-
istered by continuous ICV infusion at a dose of 7.5 nmol/day to female pubertal
(30 day old) rats, signifi cantly elevated LH levels at day 7 of the infusion and
modestly elevated FSH levels [ 24 ]. The experiment was repeated in pubertal rats
exposed to a 30% defi cit in calorie intake, and gonadotropin levels were signifi -
cantly elevated at day 7 to a greater degree than their fed counterparts. It is inter-
esting as to why no desensitization occurred in this experiment. One possibility is
that the route of administration (central vs. peripheral) may play a role.
Alternatively, a state of energy defi ciency seems to enhance the stimulatory effect
of kisspeptin-10 and reduces the tachyphylaxis seen with a continuous infusion of
kisspeptin-10 [ 24 ].
Tachyphylaxis to kisspeptin has also been demonstrated in sheep. A group of
acyclic non-breeding Ile de France ewes received a constant IVI of 600 nmol of
murine kisspeptin-10 over 48 h (12.6 nmol/h). Plasma LH was signifi cantly elevated
at 2 h, yet, by 48 h, plasma LH levels were similar to placebo. Importantly, 80% of
the ewes receiving murine kisspeptin-10 by constant infusion ovulated as compared
with only 17% of the ewes which had received placebo alone. This data suggests
that kisspeptin-10 can induce ovulatory LH surges (which occurred ~30 h after the
start of kisspeptin administration), despite desensitization to the effects of kiss-
peptin on LH secretion by 48 h, perhaps as a result of an initial stimulatory effect on
gonadotropin secretion [ 25 ].
In the Syrian hamster, reproductive activity and hypothalamic Kiss1 expression
are reduced during short day (SD) winter-like conditions. Furthermore, this effect is
reversed by chronic central administration of murine kisspeptin-10 at 6 nmol/day
for 4 weeks [ 26 ]. In contrast, a chronic SC infusion of 10 nmol/day of human kiss-
peptin-54 to male SD hamsters for 28 days failed to increase testicular weight and
plasma testosterone. However, twice daily IP injection of 10 nmol kisspeptin for 5
weeks increased testicular weight twofold and tended to increase plasma testoster-
one [ 27 ]. Therefore, kisspeptin may be a pivotal regulator of seasonal reproduction,
but the regimen of administration is critical for determining whether tachyphylaxis
is encountered, at least in SD hamsters.
In summary, desensitization to the effects of kisspeptin has been observed from
as early as 3 h after onset of continuous administration and is likely occurring at the
level of the kisspeptin receptor. Desensitization does not usually occur with repeated
administration of kisspeptin at intervals of 30-75 min, which may possibly mimic
the frequency of endogenous kisspeptin pulsatility [ 18 ]. Repeated administration at
12 hourly frequencies results in tachyphylaxis in some, but not all, studies, and
appears to be associated with higher dosages of kisspeptin. Tachyphylaxis in
response to kisspeptin is also recognized during repeated administration of
kisspeptin-54 to women with hypothalamic amenorrhoea and is an important con-
sideration for development of therapeutic dosing regimens [ 28 ].