Effects of Kisspeptin on Hormone Secretion in Humans - Kisspeptin Signaling in Reproductive Biology - page 94

receive a control injection of vehicle without kisspeptin. These decreases in LH
could lead to the nonsensical conclusion that the pituitary gland is extracting LH
from the circulation, but in reality they refl ect the ongoing degradation of circulat-
ing LH between LH pulses. Alternatively, if an endogenous LH pulse occurs around
the same time as kisspeptin administration, it may be incorrectly attributed to kiss-
peptin. These issues may have resulted in some of the discrepancies seen within and
between studies. At the same time, however, studies in reproductively normal
subjects provide an important advantage—the ability to study interactions between
kisspeptin and the endogenous reproductive endocrine machinery.
Dose-Responsive Stimulation of Gonadotropin Secretion
in Healthy Men
The fi rst use of kisspeptin in human studies was reported by Dhillo et al. [ 13 ]. In
their study, healthy male volunteers received 90-min infusions of kisspeptin-54.
Infusion rates in the fi rst 30 min ranged from 0.125 to 40 pmol/kg/min; the rate was
then halved for the remaining 60 min of the infusion (for cumulative doses ranging
from 0.0075 to 2.4 nmol/kg). These short infusions of kisspeptin-54 resulted in
dose-dependent increases in plasma LH, with the dose-response curve reaching a
plateau at ~8 pmol/kg/min (cumulative dose 0.48 nmol/kg).
The decapeptide isoform of kisspeptin similarly stimulates gonadotropin secretion
in healthy men in a dose-dependent fashion. George et al. [ 24 ] administered single
intravenous boluses of kisspeptin-10 with doses ranging from 0.0077 to 2.3 nmol/kg.
The plateau of the dose-response curve was reached at a dose of 0.23 nmol/kg.
Intriguingly, the highest dose tested in this study (2.3 nmol/kg) resulted in a smaller
increase in LH than the 0.23 or 0.77 nmol/kg doses. This result raises the possibility
that high doses of kisspeptin may induce desensitization of its receptor, a phenome-
non that has been observed in vitro [ 25 ], ex vivo [ 26 ], and in vivo [ 27 - 29 ]. However,
these studies and other studies in humans (see section “ Effects of Chronic Kisspeptin
Administration in Women with Hypothalamic Amenorrhea ”) suggest that desensiti-
zation occurs more slowly, requiring hours to days of exposure. Furthermore,
Jayasena et al. [ 14 ] found in very similar protocols that single intravenous boluses of
kisspeptin-10 at doses of 0.3, 1, 3, and 10 nmol/kg IV ×1 all produced a similar rise
in LH, without a decrease in the LH response at higher doses of the decapeptide.
These discrepant results may have been due to variations in baseline LH discussed
above; thus, further study will be needed to determine whether short-term desensiti-
zation of the kisspeptin receptor occurs in humans.
A rough estimate of endogenous kisspeptin secretion can be made by comparing
the size of LH pulses induced by exogenous kisspeptin to the size of endogenous
LH pulses. This was done in a study that incorporated an extended period of blood
sampling to measure endogenous reproductive endocrine activity prior to kisspeptin
administration (Fig. 5.1 ) [ 11 ]. The amplitude and area-under-the-curve (AUC) of
LH pulses induced by kisspeptin-10 at 0.24 nmol/kg IV ×1 were on average larger