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In-Depth Information
Kisspeptins Are Critical for the Positive Feedback
Preovulatory GnRH/LH Surge
A Case for the AVPV in Rodent Species
In mice and rats, estradiol stimulates Kiss1 expression in the AVPV [ 21 , 25 , 53 , 56 ].
In these species, the GnRH/LH surge is generated by estrogen-sensitive cells in
the AVPV [ 31 , 42 - 44 ]. Moreover, lesions of the AVPV can block the surge in
rats [ 66 ]. This and other evidence strongly suggest the sexually differentiated
population of Kiss1 cells in the AVPV provides the conduit for positive feedback
signals to reach GnRH neurons in rodent species. At the time of the preovulatory
GnRH/LH surge (the evening of proestrus), Kiss1 expression in the AVPV of
mice and rats is upregulated, and these cells also become transcriptionally acti-
vated (showing an induction of Fos) (Fig. 13.5 ) [ 21 , 25 , 67 ]. Moreover, recent
data show that the GnRH/LH surge can be blocked in rats with a central infusion
of a kisspeptin antagonist [ 68 ], and Kiss1R knockout mice are unable to mount
an LH surge in response to estradiol treatment designed to induce positive feed-
back [ 67 ]. Similarly, in mice with targeted deletions of ER
only in kisspeptin
cells (KERKO mice), no LH surges are apparent in “postpubertal” females [ 61 ],
showing kisspeptin cells, and specifi cally ER
α
α
signaling in these cells is critical
for the surge.
It appears that a rise in Kiss1 expression in the AVPV in response to estradiol
does not always predicate a GnRH/LH surge. OVX mice treated with chronic
estradiol have elevated Kiss1 mRNA in the AVPV, but “for the most part” have
suppressed levels of LH [ 53 ]. Given that a rise in AVPV Kiss1 expression from
the morning to the evening of proestrus in rats is seen in the face of relatively
constant levels of estradiol [ 21 ], it is hypothesized that other inputs, namely, cir-
cadian signals, also regulate AVPV Kiss1 expression (discussed in greater detail
in Chap. 18 ). Projections from the suprachiasmatic nucleus (SCN) to the AVPV
are known to constrain the GnRH/LH surge to a circadian onset [ 69 , 70 ]. Not
surprising then, Kiss1 expression and activation in the AVPV of estradiol treated
mice also show a circadian pattern in synchrony to the timing of the GnRH/LH
surge [ 71 ]. In hamsters, it has been shown that the SCN targets AVPV kisspeptin
neurons via vasopressinergic projections [ 72 ], and recent data in rats show it is
the dorsomedial SCN that times Kiss1 expression in the AVPV to be in phase
with the LH surge [ 73 , 74 ]. This circadian activation of Kiss1 in the AVPV also
appears to be estrogen dependent [ 71 ]. Overall, it is clear that kisspeptin neurons
within the AVPV region of the mouse and rat are stimulated by estradiol and well
placed to provide critical inputs to GnRH neurons to stimulate the preovulatory
GnRH/LH surge.
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