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The GnRH Pulse Generator, Stress, and Kisspeptin
The dynamics of the pulsatile secretion of GnRH are believed to be controlled by
a neural construct, probably resident within the mediobasal hypothalamus
(MBH), termed the “GnRH pulse generator” [
54
]. The discovery of kisspeptin as
a powerful and indispensible GnRH secretagogue, and the ensuing surge of aca-
demic discoveries linked to kisspeptin signaling, provide ample grounds on
which to base the hypothesis that ARC kisspeptin neurons that coexpress neuro-
kinin B (NKB), dynorphin A (Dyn), and the alpha subtype of the estrogen recep-
tor (ER
) are the substrate of the GnRH pulse generator. These so-called KNDy
neurons generate stimulatory and inhibitory signals to downstream mediators of
reproductive function, provide estradiol-sensitive feedback to GnRH neurons,
and seem to relay a wide variety of physiological and environmental stimuli to
the HPG axis. Furthermore, the hypophysial GnRH and systemic LH pulses, as
well as multiple electrophysiological manifestations of the GnRH pulse genera-
tor, serve as components of what can be described as a detailed bioassay for the
many extrinsic stimuli that infl uence the HPG axis. For this reason, the study of
the GnRH pulse generator is an indispensible tool for addressing the interactions
of the stress system and the HPG axis.
The regulation of kisspeptin signaling by stress neural networks is evident in
adult as well as peripubertal animals, despite a decline in ARC and mPOA kiss-
peptin expression following puberty [
18
,
55
]. In adult female rats treated with LPS,
levels of
Kiss1
and
Kiss1r
mRNAs were decreased in the ARC and mPOA, in asso-
ciation with a suppression of GnRH pulse generator frequency (Figs.
20.3
and
20.4
)
[
35
]. Administration of kisspeptin reversed the reduction in serum LH levels associ-
ated with acute infl ammation, and the LPS-induced suppression of LH secretion
and
Kiss1
mRNA expression are blocked by the anti-infl ammatory drug, indometh-
acin [
56
]. Adult male rats treated with LPS have less abundant kisspeptin-
immunoreactive cell bodies in the ARC than saline-injected controls, and the
LPS-induced reduction in LH and testosterone (T) secretion in this animal model is
independent of the anorexic effects of infl ammation [
57
].
Adult female rats treated neonatally with LPS show decreased
Kiss1
but elevated
Kiss1r
mRNA expression in the mPOA (Fig.
20.1
) [
18
]. The same repercussions are
observed following acute or chronic CORT administration in adult female rats but with
identical changes in
Kiss1
/
Kiss1r
expression extending to the ARC (Fig.
20.5
) [
35
].
Furthermore, such early life stress exposure programs the stress response in adult-
hood by inducing chronic hypercorticosteronemia [
33
] and upregulating the mPOA
expression of
CRF
-
R1
mRNA in response to acute homotypic stress exposure [
58
].
Such programming evidently sensitizes the animals to stress exposure in later life,
with augmented stress-induced CORT secretion [
33
], disrupted estrous cyclicity [
34
],
and suppression of the GnRH pulse generator [
58
] in rats treated neonatally with
LPS than in saline-treated controls. On the contrary, neonatal LPS challenge in male
rat pups attenuated the response to homotypic stress challenge in adulthood by
restricting the increase in hypothalamic and testicular expression of mRNA encoding
the proinfl ammatory cytokines TNF-
α
α
and IL-1
β
in response to LPS injection in
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