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Desensitization to the Effects of Kisspeptin with Persistent
(Chronic) Administration
A number of hormones are subject to tachyphylaxis, where the stimulatory effects
are diminished with continued administration. A prime example is GnRH, where
initial stimulation is replaced by inhibition after continuous non-pulsatile admin-
istration [
20
]. Similarly, there is evidence that the stimulatory effects of exogenous
kisspeptin diminish with persistent administration. An important study by
Seminara et al. demonstrated the phenomenon of tachyphylaxis in primates. In the
primed male agonadal Rhesus monkey model, human kisspeptin-10 was adminis-
tered as a 10
µ
g (7.7 nmol) IV bolus, followed by a continuous 98 h infusion of
100
g/h (77 nmol/h). The initial IV bolus increased LH levels twofold compared
with the preceding GnRH priming dose (0.15
µ
g/min for 2 min every hour).
Plasma LH levels peaked 1-2 h after the start of the constant infusion, reaching a
level ~2.5-fold higher than initial LH levels. However, LH levels then declined,
despite continued exposure to kisspeptin-10, suggesting that desensitization to the
stimulatory effects of kisspeptin-10 had occurred [
21
]. During the fi nal 3 h of
human kisspeptin-10 infusion, an IV bolus of GnRH,
N
-methyl- d -aspartate
(NMDA, a glutamate agonist which stimulates GnRH secretion), or human kiss-
peptin-10 was administered. Although NMDA and GnRH each elicited LH secre-
tion, kisspeptin-10 failed to do so, suggesting that the lack of effectiveness of
kisspeptin-10 administration was not due to a failure of GnRH secretion or reduced
pituitary sensitivity to GnRH. This indicates that the inability of human kiss-
peptin-10 to elicit an LH response after continuous infusion may be due to down-
regulation at the level of the kisspeptin receptor. The authors reported that
responsiveness to kisspeptin-10 was recovered at approximately 21 h after the
infusion had concluded [
21
].
Desensitization to chronic kisspeptin has also been demonstrated in rodents.
Kisspeptin-10 administered IP twice daily to 35-day-old male pre-pubertal rats for
12 days, at doses of 15 pmol, 1.5 nmol, and 1.5
µ
mol, reduced plasma LH and tes-
tosterone at the two higher kisspeptin doses, when compared with controls (FSH
remained unaltered). These data suggest that twice daily IP kisspeptin-10 at doses
of at least 1.5 nmol in pre-pubertal rats resulted in tachyphylaxis. Similarly, a con-
tinuous SC infusion of kisspeptin-54, at 50 nmol/day via a subcutaneous mini-
pump, for 13 days in adult rats also resulted in inhibition of LH secretion [
22
,
23
].
To ensure that the observed reduction in LH and FSH stimulation with chronic
kisspeptin administration was not due to peptide degradation in the mini-pump,
bioactivity studies were performed to demonstrate equivalent potency of freshly
prepared kisspeptin-54, and of kisspeptin-54 that had been incubated in a mini-
pump for 14 days at 37°C [
7
]. In another study examining the time-course of desen-
sitization, plasma LH levels were increased ~15-fold after 6 h of constant SC
kisspeptin-54 administration, ~10-fold after 12 h, but only ~2-fold after 24 h.
Plasma FSH showed a similar desensitization pattern, being elevated ~3.5-fold at
µ
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