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[
44
] (discussed more later). Additionally, the functional signifi cance, if any, of the
sexual dimorphism in the ARC
Kiss1
neuronal population during neonatal and juve-
nile development is completely unknown, especially since the reproductive axis is
essentially quiescent at this time.
Some non-rodent species, such as the sheep, display clear adulthood sex differ-
ences in kisspeptin cells in the ARC. Ewes display a greater number of
Kiss1
cells
in the ARC than adult males [
67
]; this may be due to differences in the functional
roles of
Kiss1
cells in the ARC/INF of rodents vs. sheep. However, as of yet, no
direct comparison has been made between adult ewes and rams with equivalent sex
steroid levels. Additionally, while prenatal androgen treatment reduced NKB and
DYN expression in the ARC in adult sheep, this prenatal treatment did not alter
ARC
Kiss1
expression, which remained sexually dimorphic [
67
]. Thus, there may
be different critical periods for the sexual differentiation of these ARC genes, but it
is also possible that the ovine ARC
Kiss1
system is not affected by prenatal sex
steroids. Dissimilarities between species may be due to the difference in the role of
the ARC; while ARC kisspeptin cells in rodents may mediate negative feedback
regulation of GnRH secretion, which is not sexually dimorphic [
6
,
22
,
46
,
51
,
118
],
the same kisspeptin population in sheep appears to be key for
both
negative feed-
back
and
positive feedback (i.e., the preovulatory GnRH surge) [
51
,
121
-
124
].
Similar sex differences in kisspeptin expression have been recently reported in
humans in the INF, as well as the POA, with females showing greater number of
cells than males in each region [
125
]. However, note that in these human studies,
regulatory factors that are known to alter kisspeptin levels, such as circulating sex
steroids, metabolic status, stress hormones, and circadian status, were not controlled
for and could differ dramatically between subjects, thereby confounding the results.
Whether non-human primates display adult sex differences in ARC/INF kisspeptin
levels is currently unexamined [
126
].
Regulation of ARC Kiss1 Neurons by Gonadal and Non-gonadal
Factors During Development
As noted earlier, under normal developmental conditions, the rodent ARC displays a
dense network of kisspeptin-ir fi bers that likely originate from both the ARC and the
AVPV/PeN. Supporting the hypothesis that some of these fi bers are projections from
the AVPV, data has shown that when gonadal hormones are removed during develop-
ment, whether by GDX or genetically, as in the case of the
hpg
and KERKO mice,
the number of kisspeptin fi bers detected in the ARC are reduced in adulthood
[
10
,
62
,
94
]. These data also suggest that gonadal steroids during development are
necessary for either the physical development of kisspeptin fi bers (organizational
effects) or for the transient expression of kisspeptin protein within the cells and fi bers
(activational effects). Considering that the number of kisspeptin fi bers in the ARC
was restored in adult
hpg
mice treated with E
2
, it seems likely that these kisspeptin
fi bers develop normally but only contain detectable levels of kisspeptin under the
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