Effects of Kisspeptin on Hormone Secretion in Humans - Kisspeptin Signaling in Reproductive Biology - page 97

pulses in preovulatory and mid-luteal women, similar to what had been observed in men
[ 31 ]. However, in the early follicular phase, kisspeptin-induced pulses were comparable
in size to endogenous pulses [ 31 ]. These results suggest that the dose of kisspeptin
0.24 nmol/kg was slightly supraphysiologic in preovulatory and mid-luteal women, as it
was in men, but may have been more physiologic in women in the early follicular phase.
The differences in the size of the LH response to exogenous kisspeptin in differ-
ent phases of the menstrual cycle mirrors those seen in response to exogenous
GnRH, with modest responses in the early follicular phase, larger responses in the
luteal phase, and very large responses in the late follicular/preovulatory phase [ 34 ].
Whether changes in pituitary sensitivity to GnRH can fully account for the differ-
ences in the size of the LH response to kisspeptin across the cycle, or whether
GnRH neuronal responsiveness to kisspeptin also changes across the cycle, remains
to be determined. The latter is likely to be true, as estradiol has been shown to
enhance the GnRH response to kisspeptin in various models [ 35 - 37 ].
In the early follicular phase, kisspeptin-10 elicited only small and inconsistent
responses [ 14 ] and kisspeptin-54 appeared to elicit only a late response and not an
acute response [ 15 ]. These results raise the possibility that GnRH neurons are rela-
tively resistant to kisspeptin in this phase. However, even large doses of kisspeptin-
10 failed to elicit a response in early-follicular women [ 14 ]. This suggests an
alternative possibility: that endogenous kisspeptin secretion already provides near-
maximal stimulation of the GnRH neurons in the early follicular phase, such that
they have only a limited capacity to mount an acute response to additional
exogenous kisspeptin. If so, the early follicular phase would be unique in providing
greater kisspeptin “tone” than other phases of the menstrual cycle. Because the
early follicular phase is characterized by a relatively low concentration of sex
steroids [ 30 ], this would be consistent with observations in rhesus monkeys that
kisspeptin secretion is negatively regulated by estradiol [ 38 ].
In summary, while studies in women have used a wide array of kisspeptin iso-
forms and doses and routes of administration of kisspeptin, the results of these studies
appear to refl ect differences in the duration of kisspeptin exposure resulting from
these various protocols, with sustained exposure to kisspeptin inducing similarly
sustained release of GnRH. Moreover, the response of exogenous GnRH neurons to
kisspeptin varies across the menstrual cycle, being large in preovulatory women,
intermediate in luteal-phase women, and markedly attenuated in follicular-phase
women. It remains to be determined whether differences in the sex-steroid milieu or
other factors are responsible for these differences in kisspeptin responsiveness.
Stimulatory Effects of Kisspeptin in Women
with Hypothalamic Amenorrhea
In addition to healthy adults, patients with reproductive disorders have been studied
in kisspeptin-administration protocols. One disorder that has been explored exten-
sively is functional hypothalamic amenorrhea (HA) in women. HA results from the