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brain at least, that kisspeptin cells communicate to neurons producing nitric oxide
in the POA, and this is another indirect means by which kisspeptin signals from the
ARC might be relayed to GnRH cells [
32
].
Kisspeptin and the Feedback Effects of Estrogen
Kisspeptin cells in the ARC are involved in transmission of both negative and positive
feedback signals to GnRH cells in the sheep, which is different to the case in the
rodent, where positive feedback involves the AVPV population of kisspeptin cells
and negative feedback is effected through the ARC cells [
33
]. In the ewe, the fact that
the positive feedback signal is initiated in the ARC, not the POA, was indicated by
estrogen implant studies, coupled with measures of GnRH secretion [
34
]. The kiss-
peptin cells are those ARC neurons most likely to be involved; these cells show an
upregulation in gene expression and peptide production in the late follicular phase of
the estrous cycle [
35
,
36
] and robust c-Fos labeling (as an index of neuronal activa-
tion) in response to estrogen injection [
36
]. Regarding the latter, this is a signal event
that causes a time-delayed surge in GnRH and LH secretion [
37
], which causes ovu-
lation. In addition to this
initiation
event in the ARC that culminates in GnRH/LH
surge secretion, the POA kisspeptin cells are activated at the time of the surge,
facili-
tating
the positive feedback event [
38
]. This latter observation is interesting since
only 50 % of the POA kisspeptin neurons are seen to co-express ER
in the ewe [
20
].
A fundamental question is how it is possible for one set of neurons, viz. ARC
kisspeptin neurons, to mediate
both
negative and positive feedback effects of estro-
gen in the sheep. One way to come to terms with this is to consider the positive
feedback event to be transient, whereas negative feedback is operative on a continu-
ous basis. Thus, when ovariectomized ewes are challenged with a single, acute
intravenous injection of estradiol-17
α
, the ARC kisspeptin cells are activated (c-Fos
labeling) within 1 h, and this leads to a surge in GnRH/LH secretion (positive feed-
back) [
36
]. On the other hand, when ovariectomized ewes receive constant-release
estradiol-17
β
implants, for a period of 2 weeks, the same population of ARC kiss-
peptin cells shows reduced function (negative feedback) (Fig.
19.1
) [
36
].
It should also be appreciated that GnRH neurons are also controlled by a wide
variety of cells in the brainstem, mid-brain, hypothalamus, and forebrain [
39
-
42
].
Convergent pathways from different regions of the brain may regulate GnRH cells
through polysynaptic pathways. The fact that estrogen feedback may involve cells
other than kisspeptin cells is indicated in a large number of studies, but not reviewed
here. An example, however, of one such pathway is the estrogen-receptive A1 nor-
adrenergic neurons of the brainstem, which project to the bed nucleus of the stria
terminalis (BNST) and POA, and may provide direct input to GnRH cells [
40
,
43
].
These noradrenergic cells appear to be involved in estrogen feedback, since there is
evidence of noradrenaline release in the POA at the time of the estrogen-induced
LH surge in the ewe [
44
], as in other species, such as the rat [
45
]. These other cir-
cuits should be kept in mind when considering control of reproduction by kiss-
peptin, if for no other reason than to take account of the multifaceted regulation of
β
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