Sex Steroid Regulation of Kisspeptin Circuits - Kisspeptin Signaling in Reproductive Biology - page 272

the ARC are prime candidates to mediate these feedback effects. Importantly, in the
ovine species, kisspeptin-expressing cells in the ARC are more abundant in females
than males [ 47 ], which likely relates to a role in positive feedback. In primates, clas-
sical studies in rhesus monkeys where the mediobasal hypothalamus was surgically
isolated from the rest of the brain show no interference in either estrogen negative
or positive feedback [ 48 - 50 ]. While such data convey the likely importance of ARC
kisspeptin cells and potentially eliminate a critical role for the POA kisspeptin cells,
in sex steroid feedback, an active role for the POA cannot be ruled out. Bilateral
lesions to the POA in monkeys compromised positive feedback [ 51 ]. Similar results
were also noted after separation of the anterior hypothalamus and mediobasal hypo-
thalamus [ 52 ]. Thus, in the primate, the anterior hypothalamic nuclei (potentially
kisspeptin cells in the POA) may play a role in mediating some aspects of sex ste-
roid feedback control. Whether there is a sex difference in kisspeptin expression in
primates has yet to be determined.

Sex Steroid Regulation of Kiss1 in Females

Estradiol robustly and differentially regulates the expression of Kiss1 mRNA in a
site-specifi c manner. These data were uncovered using in situ hybridization, which
allows both quantifi cation and histological mapping of Kiss1 mRNA. In the ARC,
ovariectomized (OVX) female mice show a pronounced upregulation in the number
of Kiss1 mRNA-expressing cells, which is prevented by estradiol replacement
(Fig. 13.2 ) [ 53 ]. In striking contrast, in the AVPV, OVX mice show reduced expres-
sion of Kiss1 mRNA, and estradiol replacement stimulated its expression (Fig. 13.2 )
[ 53 ]. Similar data were subsequently forthcoming in female rats [ 21 ]. These fi nd-
ings led to the hypothesis that kisspeptin neurons in the ARC transmit signals to
GnRH neurons pertinent to estrogen negative feedback, while kisspeptin cells in the
AVPV relay estradiol signals for positive feedback.
In rodents, virtually all kisspeptin cells in the ARC and AVPV express ER α [ 21 ,

53 ], and the importance of ER expression on kisspeptin neurons in females is

unquestionable. Unlike female wild-type mice, female ER

α

knockout mice are
unable to regulate AVPV or ARC Kiss1 mRNA expression in the face of OVX and
estradiol replacement (Fig. 13.3 ) [ 53 ]. Similarly, in female rats, the selective ER

α

α

agonist, propyl pyrazole triol, is able to suppress hypothalamic Kiss1 mRNA expres-
sion, as determined by RTPCR (however, this data lack anatomical specifi city) [ 54 ].
Interestingly, the selective ER agonist, diarylpropionitrile, was unable to inhibit

the post-OVX rise in Kiss1 mRNA [ 54 ], and so the role of this estrogen receptor
subtype for kisspeptin regulation is questionable. Despite this, a surprisingly signifi -
cant proportion, but not the majority, of ARC and AVPV kisspeptin neurons express
ER

β

knockout mice, the ability of OVX and estradiol
replacement to regulate Kiss1 mRNA expression is maintained [ 53 ]. These data
reinforce the notion that ER

β [ 53 ]. However, in ER β

β does not play a signifi cant role in estrogen feedback