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LH was increased in a dose-dependent manner after 60 and 180 min of incubation.
Even so, the relative contribution of direct pituitary effects to the potent LH releas-
ing effect of kisspeptin-10 in vivo is likely to be small, as in vitro doses of kiss-
peptin required to generate LH release from pituitary cells are much higher when
compared with in vivo kisspeptin dosages. Taken together, this suggests that the
primary effect of kisspeptin on gonadotropin release in vivo occurs in the brain via
GnRH release [
5
].
The sheep is an ideal model to study the effects of kisspeptin on the pituitary,
because the pituitary gland is large and a hypothalamo-pituitary disconnection
(HPD) model allows for exploration of direct actions of kisspeptin on GnRH-
stimulated gonadotropin secretion in vivo. The HPD procedure removes all neural
inputs to the median eminence, but gonadotropin secretion can be restored by pul-
satile IV administration of GnRH. The kisspeptin receptor is expressed in pituitary
cultures from ewes (although only during the follicular phase of the estrous cycle).
Incubation of ovine pituitary cells with kisspeptin increased the concentration of
LH in culture media by 80%, compared with control treatment. Despite this in vitro
fi nding, kisspeptin was unable to stimulate in vivo LH secretion in GnRH-replaced
ovariectomized HPD ewes. Furthermore, while low levels of kisspeptin were
detected in the ovine hypophyseal portal circulation, these kisspeptin levels did not
change during an estrogen-induced LH surge. Hence, the in vitro stimulatory effect
of kisspeptin on isolated pituitary cultures may not relate to kisspeptin's signaling
in vivo [
41
].
In pigs, anterior pituitary cells have been harvested from 6-month-old triple cross
bred (Landrace × Large White × Duroc) barrows (castrated male pigs) and incubated
in 10 nM GnRH or 10-1,000 nM kisspeptin-10. The 1,000 nM dose of kisspeptin-10
signifi cantly increased in vitro porcine LH levels by 31%, compared with the con-
trol. However, the LH-releasing potency of kisspeptin-10 in porcine anterior
pituitary cells was far less potent than that of 10 nM of GnRH [
42
]. Cultured bovine
anterior pituitary cells incubated with kisspeptin-10 secreted LH, but only at a high
kisspeptin concentration of 1,000 nM [
22
]. Bovine anterior pituitary cells from
7-week-old male calves incubated with human kisspeptin-10 released LH, when
also pre-incubated with estradiol and testosterone, but not progesterone [
43
].
Overall, despite the presence of kisspeptin receptor in the pituitary, most of the
data support the theory that the predominant action of kisspeptin is at the hypothala-
mus, to increase GnRH release, which subsequently stimulates gonadotropin
release. Any direct effects of kisspeptin on the pituitary gland are likely to be negli-
gible in vivo.
Comparison of Different Kisspeptin Isoforms
The 145 amino acid gene product of the
Kiss1
gene is post-translationally cleaved
into peptides of varying amino acid lengths, including kisspeptin-54, kisspeptin-14,
kisspeptin-13, and kisspeptin-10. Kisspeptin-10 is identical between humans and
Macaque monkeys; the sequence of kisspeptin-10 in the rat, mouse, pig, cow, and
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