Effects of Kisspeptin on Hormone Secretion in Humans - Kisspeptin Signaling in Reproductive Biology - page 103

Erratic LH Secretion Generated by Sustained Infusions
of Kisspeptin
Alterations in the pattern of GnRH pulse generation have also been observed in
studies of sustained infusions of kisspeptin [ 24 ]. In one study, healthy men received
22.5-h infusions of kisspeptin-10 at a rate of 3.1 nmol/kg/h. LH increased across the
fi rst several hours of the infusion then remained elevated for the remainder of the
infusion. There were several notable features of the pattern of LH secretion during
the kisspeptin infusion. One is that desensitization was not observed. In rats, continu-
ous intracerebroventricular administration of kisspeptin has been shown to cause
desensitization to kisspeptin [ 29 ]. Similarly, continuous intravenous administration
of kisspeptin-10 to juvenile and adult male rhesus monkeys at rates of ~25-30 nmol/
kg/h causes desensitization, with LH starting to decline within 4 h of the start of the
infusion [ 27 , 28 ]. As detailed in the section below, chronic administration of kiss-
peptin-54 to women caused desensitization to kisspeptin over several days [ 43 ].
Thus, the phenomenon of desensitization has been observed in several mammalian
species, including humans. The lack of desensitization in healthy men who received
kisspeptin-10 at 3.1 nmol/kg/h ×22.5 h may be due to the lower rate and/or shorter
duration of the infusion compared to these other studies.
A second notable feature of the pattern of LH secretion in response to the kisspeptin
infusion was that it was erratic, with occasional discrete pulses but mostly apparently
chaotic variation. This erratic pattern of LH secretion resembles that observed in stud-
ies in which repetitive boluses of GnRH were given to men with GnRH defi ciency at
high frequencies [ 22 ]. While discrete LH pulses were visible when GnRH was given
every 1 h, when the frequency of GnRH administration was increased to every 30 min
or every 15 min the LH pattern became more chaotic, with peaks and valleys of LH
that did not correlate with pulses of exogenous GnRH [ 22 ]. Thus, while it is tempting
to interpret the presence of LH pulses during a continuous infusion of kisspeptin as
demonstrating that pulsatile secretion of GnRH can occur in the absence of pulsatile
kisspeptin, because the one-to-one concordance between LH pulses and GnRH pulses
is lost under conditions of high GnRH pulse frequency and continuous GnRH infu-
sions, further investigation is required to address this issue conclusively.
Effects of Chronic Kisspeptin Administration in Women
with Hypothalamic Amenorrhea
To date, the effects of chronic (>24 h) administration of kisspeptin have been
explored only in women with HA. As described above, Jayasena et al. found that
acute exposure to kisspeptin caused elevations of FSH, LH, and estradiol in women
with HA [ 43 ]. Encouraged by this fi nding, the same group proceeded to study the
effects of chronic kisspeptin administration in women with HA by administering
kisspeptin-54 6.4 nmol/kg subcutaneously twice daily [ 43 ]. Though this dose of
kisspeptin caused a rise in LH on the fi rst day, after 2 weeks of treatment kisspeptin