Kisspeptin and Puberty in Mammals - Kisspeptin Signaling in Reproductive Biology - page 261

knockout of ER in kisspeptin neurons exhibit elevated Kiss1 mRNA levels in ARC

at a prepubertal age, and this is associated with high circulating concentrations of
LH (and presumably E 2 ) and a dramatic advancement of the age of vaginal opening
[ 50 ]. Interestingly, in contrast to the mRNA data, kisspeptin immunoreactivity in
the ARC was greatly reduced in the conditional knockout, suggesting perhaps
enhanced release of kisspeptin. Thus, in the case of the female mouse, it seems
reasonable to conclude that the site of the prepubertal ovarian steroid suppression
on pulsatile GnRH release is on the GnRH pulse generating mechanism itself, and
specifi cally on kisspeptin (KNDy) neurons in the ARC. This view is consistent with
the long-standing “differential sensitivity to E 2 ” theory, which has been proposed in
female rats and sheep [ 97 - 100 ]. During the postnatal period through the juvenile
period, the hypothalamus (presumably the GnRH neurosecretory system) is inhib-
ited by E 2 , and, sometime prior to puberty, the GnRH pulse generating mechanism
in the ARC escapes from suppression by E 2 . It has been proposed that this escape is
the result of an E 2 -induced increase in activity of kisspeptin neurons in the AVPV,
which in turn amplifi es GnRH neuronal activity, leading to puberty onset [ 36 , 49 ,
50 ]. The precise mechanism by which the initial prepubertal elevation of E 2 is trig-
gered in non-primate species, however, is unknown. (Note that, in women and
female rhesus monkeys, a similar escape of E 2 -dependent inhibition of GnRH
release occurs well after the initiation of puberty onset, between menarche and fi rst
ovulation [ 101 - 103 ]).

α

Summary

In this chapter, we have reviewed progress regarding the relationship between kiss-
peptin and puberty onset, and have proposed a novel hypothesis for the role of kis-
speptin signaling in controlling the timing of this major event in postnatal
development. We posit that the profound impact of loss-of-function mutations in the
genes encoding either kisspeptin or its receptor on the onset and progression of
puberty in all species can be attributed primarily to the critical role of ARC kiss-
peptin neurons in the generation of pulsatile GnRH release, which is obligatory for
pubertal activation of the pituitary-gonadal axis. According to this hypothesis, kiss-
peptin neurons do not determine the timing of puberty (see Fig. 12.3 ). Rather, this
important developmental event is achieved by upstream neuronal mechanisms that
govern the timing of the pubertal activation (rodents) or reactivation (primates) of
robust pulsatile GnRH release at the end of the juvenile phase of development.
Validation of this hypothesis requires future studies.

Acknowledgements Supported by grants R01 HD15433 and R01 HD11355 for ET, R01 HD
013254 and U54 HD 08160 for TMP, T32 HD041921 for KAG, and P51 0D011106 for WNPRC.