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mechanisms dictate the timing of puberty by suppressing GnRH pulse generation.
This being the case, loss-of-function mutations in KISS1 / Kiss1 or KISS1R / Kiss1r ,
or ablation of neurons expressing either kisspeptin or its receptor, would likely lead
to a loss or impairment in GnRH pulsatility that secondarily results in delayed or
absent puberty and infertility, regardless of species. While this is indeed the case in
situations where the genes have been manipulated either spontaneously or experi-
mentally [ 1 , 9 - 11 , 50 , 83 ], interestingly, embryonic ablation of kisspeptin cells in
mice did not dramatically infl uence the timing of puberty or prevent fertility [ 45 ]. It
should be noted that failure to change the timing of puberty in this study may be due
to the 5% of kisspeptin neurons in the AVPV that escaped ablation [ 45 ]. In the con-
text of the results of the study employing kisspeptin neuron ablation, Kiss1 or Kiss1r
null mice exhibit some degree of GnRH release as they age [ 83 ]. Therefore, the
difference in the phenotypes between these two models may be quantitative, and
perhaps explained by differences in the extent to which the GnRH neuronal network
is intrinsically able to generate intermittent GnRH release following a genetic or
ablative insult to the GnRH pulse generating mechanism that normally drives
gonadotropin secretion in the adult.
The notion that kisspeptin signaling is necessary for the onset of puberty only
because of its critical role in GnRH pulse generation may be most readily appreciated
when the concept is applied to puberty in the male, where initiation of this develop-
mental event requires only robust pulsatile GnRH release to drive tonic LH and FSH
secretion. In the case of puberty onset in the human female, the validity of the idea that
KISS1 may simply be regarded as a “pulse generating” gene is tenable, because the
preovulatory LH surge is triggered by E 2 positive feedback action within the MBH-
pituitary unit to amplify pulsatile GnRH release and/or the response of the pituitary
gonadotrophs to pulsatile GnRH stimulation [ 22 ]. The situation in the female rodent
is more complex because the positive feedback action of E 2 is exerted, at least in part,
on kisspeptin neurons in the AVPV [ 31 ]. Nevertheless, as discussed above, the devel-
opment of kisspeptin neurons in the AVPV in female mice is dependent on ovarian E 2
secretion, which, in turn, is dependent on tonic gonadotropin secretion that is driven
by pulsatile GnRH release. Thus, it seems reasonable to propose that (1) the primary
role of kisspeptin signaling in the control of puberty across species may be restricted
to its crucial role in GnRH pulse generation, (2) the time of puberty onset is dictated
by kisspeptin-independent mechanisms that control the ontogeny of GnRH pulse gen-
eration, and (3) Kiss1 in the rodent may be viewed as a “surge generating gene,” as
well as a pulse generating gene (see below for further discussion).
Neuronal Substrates of Central Inhibition on GnRH
in Juvenile Primates
According to the model proposed above, the key to the mystery of puberty in pri-
mates is to understand (1) the neural substrate that underlies the gonadal steroid-
independent reduction in GnRH pulse generation from infancy to puberty, and (2)
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