Circadian Regulation of Kisspeptin in Female Reproductive Functioning - Kisspeptin Signaling in Reproductive Biology - page 392

is manipulated through pharmacology and molecular/cellular biology will help to
further establish, and clarify, the specifi c role played by this circadian timing hier-
archy in female reproduction. For example, does GnRH exhibit time-dependent
specifi city to all modulatory neurochemicals, only kisspeptin, or only positive reg-
ulators of GnRH activity? Likewise, in addition to estrogen signaling, what other
positive and negative regulators of the reproductive axis converge on kisspeptin
cells to integrate with circadian signaling and precisely time the GnRH/LH surge?
Recent evidence in mice suggests that at least GnIH acts directly on a subset of
kisspeptin cells [ 125 ], providing a mechanism for kisspeptin cell inhibition prior to
initiation of ovulation and sexual motivation. Additionally, it is unclear why the
SCN projects both directly to the GnRH and kisspeptin systems to positively drive
GnRH secretion when integration at a single locus is more parsimonious. Finally,
most studies to date investigate GnRH secretagogues (e.g., GABA, dynorphin, glu-
tamate) in isolation or pairs. Future studies applying multivariate connectomic,
proteomic, and genomic analyses to understand the complex interactions among
these systems, and their integration with circadian control, will be necessary to gain
a full understanding of the complexity underlying normal female reproduction and
apply this knowledge to disorders of puberty and infertility.
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