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interval between other endogenous pulses (interval A in Fig.
5.3
). However, in men,
this interval was found to be signifi cantly longer than the endogenous pulse interval
(Fig.
5.3
).
A second prediction of the “no resetting” model stems from the fact that kisspeptin
was given without knowledge of the timing of endogenous pulses. If kisspeptin has
no effect on the timing of endogenous pulses, then kisspeptin administration could
occur at any point within the interval between endogenous pulses, and would be
equally likely to occur early in that interval as it would be to occur late in that interval.
Thus, given a suffi cient number of observations, the average time of kisspeptin
administration should fall in the middle of the interval between endogenous pulses,
dividing this interval evenly into halves. However, the average time of kisspeptin
administration fell closer to the preceding endogenous pulse than to the subsequent
endogenous pulse (Fig.
5.3
). Thus, neither prediction of the “no resetting model” was
upheld by empirical data in men.
An alternative model, the “resetting” model, is that kisspeptin resets the GnRH
pulse generator (Fig.
5.3
). GnRH pulse generation has been shown to be a renewal
process in men, that is, the timing of a GnRH pulse depends on the timing of the
previous pulse but not of pulses prior to that [
61
]. In other words, the process of
pulse generation begins anew with each pulse, with each pulse setting a new “time
zero” that is used to determine the timing of the next pulse. In the “resetting” model,
the kisspeptin-induced pulse replaces the previous endogenous pulse as this time
zero. Thus, the next endogenous pulse would be predicted to follow the kisspeptin-
induced pulse by an interval that matches the endogenous interpulse interval. This
is precisely what was observed (Fig.
5.3
). Thus, in men, kisspeptin appeared to have
reset the GnRH pulse generator.
A potential alternative explanation for these observations is that kisspeptin may
have produced a refractory period during which the reproductive endocrine machinery
is unable to produce an LH pulse. This would result in some pulses being “skipped”
and thus create an apparent delay in the appearance of the next endogenous pulse.
However, in some individuals an endogenous pulse occurred shortly after kisspeptin
administration, arguing against a lengthy refractory period [
11
]. Furthermore, it would
be an unlikely coincidence that the duration of this refractory period would result in a
delay precisely long enough to match the prediction of the “resetting” model. Resetting
therefore remains the most parsimonious explanation for the results observed in men.
The phenomenon of resetting appears to be sexually dimorphic, as it was not observed
in women [
31
]. Previous analyses of pulse patterns in healthy adults had also suggested
differences in how men and women generate pulses of GnRH secretion [
61
,
62
].
Both the physiologic basis and the teleological explanation for these differences
remain obscure, and future studies involving manipulation of the sex-steroid milieu
and other factors may elucidate their roles in establishing these differences.
Given our minimal understanding of how GnRH pulses are generated, the mech-
anisms by which resetting could occur are unclear. Kisspeptin could have a direct
effect on the GnRH pulse generator, or it could act indirectly through GnRH, LH,
FSH, or other downstream factors. Further exploration of the effects of kisspeptin
on GnRH pulsatility may allow investigators to identify the cellular and molecular
machinery that generate GnRH pulses.
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