Sex Steroid Regulation of Kisspeptin Circuits - Kisspeptin Signaling in Reproductive Biology - page 277

Kisspeptin Controls Negative Feedback Regulation
of GnRH Secretion

Sex steroids clearly inhibit kisspeptin cells in the ARC in numerous species. Paired
with the aforementioned data linking cells in the ARC to negative feedback, kiss-
peptin cells are well placed to be central to this process. Consistent with negative
feedback, the post-gonadectomy rise in Kiss1 expression is paired with a corre-
sponding rise in LH secretion, in an attempt to increase sex steroid production [ 53 ,
56 ]. In Kiss1r knockout mice, gonadectomy and sex steroid replacement are able to
regulate Kiss1 mRNA expression appropriately, but in these mice, the subsequent
stimulation of LH release was not evident [ 17 ], even after the withdrawal of sex
steroid treatment [ 59 ] (although a modest response in FSH secretion was detect-
able), indicating the importance of kisspeptin signaling in relaying negative feed-
back. Consistent with this, LH secretion in gonadectomized rats and mice, and
pulsatile LH secretion in female monkeys and OVX sheep, is inhibited by central
administration of a selective kisspeptin antagonist [ 60 ]. These data again demon-
strate that the stimulation of GnRH/LH after gonadectomy—via removal of nega-
tive feedback regulation—is dependent on kisspeptin signaling.
Alternatively, in mice with a targeted deletion of ER only in kisspeptin neurons

(termed “KERKO” mice), gonadotropin secretion is high [ 61 ]. Indeed, in female
KERKOs, abnormally high gonadotropins cause a precocious puberty-like model
where the external markers of puberty arise 15-16 days earlier than wild-type coun-
terparts. In this model, it appears there is a chronic absence of negative feedback
causing unrestrained gonadotropin release. Importantly, in these animals the num-
ber of identifi able kisspeptin cells in the AVPV is low, but in the ARC, the number
of identifi able kisspeptin cells and the expression of Kiss1 mRNA are elevated [ 61 ],
refl ecting the absence of sex steroid feedback to these populations. These mice
illustrate both the critical role of ARC kisspeptin cells in negative feedback and the
importance of ER

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signaling on kisspeptin neurons for this process.
In goats, evidence suggests that the intrinsic GnRH pulse generator (controlled
by negative feedback) is located in the caudal ARC, where kisspeptin cell bodies are
located [ 62 ] (discussed in greater detail within this textbook). Growing evidence
also suggests ARC kisspeptin cells drive pulsatile GnRH secretion via the autosyn-
aptic activity of the neuropeptides neurokinin B (NKB) and dynorphin, which are
co-expressed in virtually all ARC kisspeptin expression neurons [ 63 ]. Neurokinin B
(stimulatory) and dynorphin (inhibitory) are proposed to coordinate the pulsatile
discharge/release of kisspeptin from the ARC [ 47 , 64 , 65 ] (discussed in greater
detail within this textbook). Thus, kisspeptin cells in the ARC are geared to receive
estrogen negative feedback signals and modulate their activity appropriately, which
in turn regulates the stimulatory control of GnRH neurons to maintain the tonic/
pulsatile secretion of GnRH and LH.

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