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Effect of Sex and Stage of Female Estrus Cycle
on Response to Kisspeptin
Interestingly, there may be sex differences in the effects of kisspeptin. Ezzat et al.
[
51
] administered kisspeptin-10 to male and female Japanese pre-pubertal calves at
5-6 months of age. Maximum LH (7.2 ng/mL vs. 17.4 ng/mL) and FSH (0.6 ng/mL
vs. 1.5 ng/mL) secretion was lower in females when compared with males [
51
].
However, it should be noted that the observed sex difference in this study might be
due to differing developmental stages, given that males and females go through
puberty at different times. Healthy adult men are more responsive to the effects of
kisspeptin-10 than adult females in the follicular phase [
7
]. In keeping with this
human data, male hamsters had greater LH responses to IP kisspeptin-10 than
females [
61
]. However, female rats were more sensitive to kisspeptin-10, as assessed
by LH stimulation, when compared with male rats [
60
]. Thus, while some studies
have reported sex differences in response to kisspeptin, the direction of the sex dif-
ference (female > male or male > female) differs between studies and species, and
the exact reasons for the observed sex differences have yet to be teased out.
The stage of adult female reproductive cycle also plays an important role in infl u-
encing sensitivity to exogenous kisspeptin. Roa et al. [
62
] centrally administered
1 nmol kisspeptin-10 to adult Wistar female rats at different stages of the estrus
cycle. Plasma LH stimulation was greatest during estrus (sixfold increase); LH
increased fourfold during diestrus, and only twofold during proestrus [
62
].
Gonadotropin responses following GnRH administration are also increased during
ovulation, due to increased pituitary sensitivity associated with high circulating
estrogen levels [
63
]. It is therefore possible that kisspeptin induces different levels
of LH secretion during the female rodent reproductive cycle, as a consequence of
differential sex steroid priming of the pituitary gland. Maximal FSH stimulation
following kisspeptin administration was observed during diestrus [
62
]. It is there-
fore important to consider that FSH secretion does not always mirror LH secretion.
Moreover, it appears clear that levels of circulating sex steroids play an important
role in modulating the effects of kisspeptin on gonadotropin secretion. In ovariecto-
mized rats, replacement of estradiol suppressed baseline LH levels, but did not
affect LH stimulation by kisspeptin-10 administration. Progesterone replacement
did not infl uence the effects of kisspeptin-10 on LH secretion. However, combined
replacement of progesterone and estrogen permitted kisspeptin to elicit a 22-fold
increase in LH secretion when compared with animals without progesterone and
estrogen replacement. Hence, progesterone replacement seems to sensitize estrogen-
replaced ovariectomized rats to the effects of kisspeptin-10 [
62
].
The reproductive axis clearly plays an important role in determining the effects
of kisspeptin in an animal. The question remains, however, if the sensitivity to
kisspeptin refl ects direct changes in GnRH sensitivity to kisspeptin, or rather, a
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