Sex Steroid Regulation of Kisspeptin Circuits - Kisspeptin Signaling in Reproductive Biology - page 283

a link between estrogen and Kiss1r remain mixed, with studies showing estrogen
inhibition [ 54 ] and others showing no effect [ 91 ]. Both these studies utilized RTPCR
and subsequently lack the specifi city of observing Kiss1r expression on GnRH
neurons. However, recent data in sheep to this end failed to observe any change
in Kiss1r expression on GnRH neurons between OVX and OVX + E animals [ 92 ].
An alternative possibility for estrogen regulation of GnRH response may relate to
the indirect effects of afferent inputs to GnRH neurons that are estrogen sensitive.
In electrophysiological recordings of GnRH neurons, blockade of ionotropic gamma-
aminobutyric acid and glutamate receptors prevented the estrogen-potentiated GnRH
response in OVX + E mice [ 11 ]. Thus, kisspeptin activation of GnRH neurons can
be gated by transsynaptic mechanisms.
Conclusions
Since 2003, kisspeptin has been cast to the forefront of neuroendocrine research,
and remarkable advances in our understanding of the reproductive axis have been
made. It is clear that kisspeptin signaling is fundamental to the reproductive system.
Specifi cally, kisspeptin cells in the hypothalamus are strong candidates to act as key
conduits providing the “missing link” in the sex steroid feedback control of GnRH
secretion. We now know that kisspeptin cells in the ARC are well placed to drive the
estrogen negative feedback signals that control the tonic pulsatile release of GnRH.
This appears to be true for multiple species. Concerning estrogen positive feedback,
which drives the preovulatory GnRH/LH surge, more rostral hypothalamic popula-
tions of kisspeptin cells in the AVPV are implicated in rodent species. In sheep and
primates, kisspeptin cells in the ARC are also poised to play key roles in the positive
feedback regulation of GnRH. Importantly, it remains to be determined if it is the
same kisspeptin cells that show both estrogen negative feedback and estrogen posi-
tive feedback responses. Growing evidence suggests the rostral POA populations in
these species may also play a role in the estrogen positive feedback process (draw-
ing comparisons to rodent species). It is still unclear exactly how kisspeptin neurons
appear to be differentially regulated by essentially the same hormonal stimulus
(estradiol). Evidence shows that classical and nonclassical estrogen signaling path-
ways are involved, but it is still unknown how the divergent pathways arise. These
and other challenges in the kisspeptin fi eld remain for future studies.
References
1. Moore CR, Price D (1932) Gonadal hormone functions and the reciprocal infl uence between
gonads and hypophysis, with its bearing on sex hormone antagonism. Am J Anat 50:13-71
2. Herbison AE, Theodosis DT (1992) Localization of oestrogen receptors in preoptic neurons
containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone-
releasing hormone in the male and female rat. Neuroscience 50:283-298