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In-Depth Information
for negative feedback, cells within the mediobasal hypothalamus are thought to be
crucial in mediating estrogen positive feedback effects on GnRH secretion [
45
,
46
].
Consistent with this,
Kiss1
expression is greatest in the caudal region of the ovine
ARC immediately prior to the GnRH/LH surge [
16
,
26
]. Moreover, transcriptional
activation of kisspeptin cells increases in the mid- and caudal ARC of OVX ewes
when treated with a positive feedback-inducing estradiol stimulus [
16
]. Thus, it
appears kisspeptin cells in the ARC are important for both estrogen negative
(as discussed above) and positive feedback effects (Fig.
13.5
). The discriminating
factor here being kisspeptin cells in the mid- to caudal region of the ARC are
involved in the estrogen positive feedback GnRH/LH surge, while kisspeptin cells
across the whole ARC appear responsive to chronic estrogen negative feedback
regulation. It is possible that discrete regions of the ARC distinguish different estrogen
stimuli (acute rise in estradiol vs. chronic levels) and transmit negative or positive
regulation of GnRH secretion. Alternatively, the same kisspeptin cells in the caudal
ARC may respond to both negative and positive feedback stimuli, possibly involv-
ing classical and nonclassical estrogen signaling pathways, as discussed below [
78
].
In this regard, it is pertinent to note that acute (surge-inducing) estradiol treatment
induced Fos expression in the vast majority of caudal ARC kisspeptin cells in sheep,
while after OVX, approximately half of the kisspeptin cells in the same region had
induced Fos expression [
16
]. Thus, it is probable that some kisspeptin cells are
responding to both positive and negative estrogen feedback signals, at least in sheep.
Similar to data in the caudal ARC,
Kiss1
expression in the ovine POA was also
greater just prior to the preovulatory GnRH/LH surge (Fig.
13.5
) [
16
]. More recent
data show transcriptional activation of kisspeptin cells in the POA during the surge
[
79
]. Because estradiol treatment appears to increase
Kiss1
expression in the ovine
POA [
14
], with similar reports in the pig [
80
], a parallel is drawn between the
ovine POA and the rodent AVPV. Moreover, these data implicate kisspeptin cells
in both the caudal ARC and the POA as central processors of the feedback effects
of estradiol that cause the GnRH/LH surge in the ovine species (Fig.
13.5
). Data
also show upregulation of
Kiss1
in the rhesus monkey ARC and POA at the time of
the GnRH/LH surge, suggesting both populations are involved in the preovulatory
GnRH/LH surge of nonhuman primates [
81
]. It is unclear exactly how POA kiss-
peptin neurons in the sheep participate in the estradiol-induced GnRH/LH surge.
Unlike the ARC or the rodent AVPV, fewer (~50%)
Kiss1
cells in the ovine POA
express ER
[
28
]. It is entirely possible that estrogen can activate these neurons
directly, but one alternative possibility is that kisspeptin cells in the POA are acti-
vated indirectly by estrogen positive feedback.
α
Mechanism for Differential Regulation
The mechanism for differential regulation of
Kiss1
expression in the ARC and
AVPV is not entirely known. Clues may arise through the search for phenotypical
differences between kisspeptin cells in the ARC and AVPV. In mice, between 50 and
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