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(containing the ARC), not the POA [ 45 , 46 ]. Thus, it appears in this species that
kisspeptin neurons in the ARC are additionally able to respond in a manner appro-
priate for positive feedback (see below).
In humans, KISS1 mRNA expression is increased in the ARC of postmenopausal
women to a similar degree to that seen in OVX cynomolgus macaques [ 30 ]. Given
that menopause results from ovarian failure, the model may be regarded as similar
to chronic OVX. These data then suggest that kisspeptin neurons in the ARC medi-
ate estrogen negative feedback in humans, as they appear to do in rodents and sheep.
Interestingly, kisspeptin neurons also populate the POA in humans [ 30 ]; however
there have been no reports of this population's regulation via estradiol or change in
postmenopausal women.
Sex Steroid Regulation of Kiss1 in Males
Testosterone regulates the expression of Kiss1 mRNA in the male hypothalamus.
Similar to estradiol regulation in females, testosterone inhibits the post-castration
rise of Kiss1 mRNA in the ARC of mice [ 56 ]. Consistent data are also apparent in
male rats [ 6 ]. Interestingly, in the male AVPV, castration reduces Kiss1 mRNA and
testosterone stimulates its expression [ 56 ]. Thus, kisspeptin neurons in the ARC can
again be assigned the task of relaying steroid (in this case, testosterone) negative
feedback. Kisspeptin cells in the male AVPV respond similarly to the female AVPV,
but we are left to ponder what physiological role they play (males normally do not
generate sex steroid positive feedback). There is a signifi cant sex difference in the
abundance of kisspeptin neurons in the AVPV, with females harboring far more
Kiss1 -positive cells in the AVPV than males [ 12 , 20 ] (discussed in greater detail in
Chap. 11 ). Nevertheless, kisspeptin cells in the male AVPV are clearly different
than those in the ARC, especially in their regulation by sex steroids, and may play
a role in other testosterone-mediated processes.
The majority of kisspeptin neurons in the male AVPV and ARC co-express
ER
and AR [ 56 , 57 ]. Unlike females, the signaling mechanisms mediating the
actions of testosterone appear to be different in the two populations of kisspeptin
cells. In the AVPV, the effects of testosterone appear to be mediated by ER
α
α
or
ER
, because estradiol treatment is able to fully mimic the effect of testosterone
(Fig. 13.4 ) [ 56 ]. Treatment with the non-aromatizable dihydrotestosterone (DHT)
had no effect, indicating no action via the androgen receptor [ 56 ]. Using ER
β
α
knockout mice, the effect of testosterone on kisspeptin regulation in the AVPV was
maintained [ 56 ], indicating ER
α
did not mediate this effect and it was therefore
possibly due to ER
. In the male ARC, both DHT and estradiol were able to mimic
the inhibitory effect of testosterone, indicating the regulation of Kiss1 here is
mediated by both estrogen receptor (most likely ER
β
) and androgen receptor
(Fig. 13.4 ) [ 56 ]. Not surprising then was that in male mice lacking ER
α
or complete
functional androgen receptor, there was no disturbance in testosterone-mediated
inhibition of Kiss1 in the ARC (with one receptor compensating for the absence of
the other) [ 56 ].
α
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