Kisspeptin and Seasonality of Reproduction - Kisspeptin Signaling in Reproductive Biology - page 412

that this mechanism involves regulation of kisspeptin cells of the ARC and, since
the treatment with exogenous kisspeptin overrides this, it allows a sustained GnRH
secretion. Another interesting fi nding of these studies was that constant infusion of
kisspeptin is effi cacious in stimulating gonadotropin secretions, but intermittent
intravenous injection was not [ 93 ]. Other work in primates has suggested that con-
stant infusion of high kisspeptin amounts causes downregulation of the kisspeptin
receptor [ 19 ]. In peripubertal female rats, circulating LH concentrations remain
elevated after 7 days of continuous cerebral infusion of kisspeptin, an effect which
is not observed in cyclic rats [ 94 ]. Therefore, it is very likely that, within a given
range of concentrations, which might vary according to the species and develop-
mental stage, continuous infusion of kisspeptin can stimulate GnRH, and hence
gonadotropin secretion, for extended periods of time. This latter observation is
especially relevant from a practical perspective, as it might lead to new treatments
to control fertility. Indeed, it was demonstrated that 24 h of constant infusion of
kisspeptin in acyclic anestrous ewes was the minimal duration required to induce
the secretion of estrogen [ 95 ] to a level known to cause positive feedback [ 96 ]. For
this to be practicable, however, we need to produce kisspeptin agonists with higher
potency than the natural molecules, but there is only one report of such a compound
with slightly higher activity than kisspeptin-10 [ 97 ]. An alternative strategy to
address the problem could be to increase the half-life of the kisspeptin molecule in
plasma, rather than its intrinsic potency. This strategy has already been applied suc-
cessfully in the case of GnRH agonist molecules used in the treatment of various
forms of cancers [ 98 ]. Generation of long-lasting agonists of kisspeptin could pro-
vide sustained stimulation of the GnRH/gonadotropic axis.
In essence, the demonstration that i.v. administration of kisspeptin can stimulate
ovulation in seasonally anestrous ewes and in prepubertal ewes [ 99 ] offers a means
of controlling reproduction in farm animals. For practical use, however, the devel-
opment of new pharmacological tools will nevertheless prove essential to devise
new strategies and make progress towards practical exploitation.
As with the issues relating to the role of kisspeptin and response to photoperiod
in hamsters, our current understanding is somewhat unclear because of differences
between the two species. Chronic central administration of kisspeptin-10 for 4
weeks to male Syrian hamsters on short days was shown to increase testis weight
and plasma testosterone to levels seen under long-day photoperiod [ 63 ]. However,
a paper by Greives et al. [ 58 ] indicated that various treatment paradigms of periph-
eral administration of kisspeptin-10 (infusion by osmotic mini-pump or daily i.p.
injection) failed to activate reproductive function in male Siberian hamsters on
short-day photoperiod. Neither did daily kisspeptin-10 injections prevent reproduc-
tive regression during transition from long days to short days. At face value, this
indicates that male Siberian hamsters are markedly different from female sheep, in
which kisspeptin infusion activates the reproductive axis in the nonbreeding season.
On the other hand, continuous treatment of Syrian hamsters with kisspeptin-54
delivered by osmotic mini-pumps did not stimulate the reproductive axis in short-
day (inhibitory) photoperiod, but intermittent treatment (two injections each day)