Effects of Kisspeptin on Hormone Secretion in Humans - Kisspeptin Signaling in Reproductive Biology - page 99

exhibited low-amplitude but detectable LH pulses. When given an infusion of
kisspeptin, the amplitude of LH pulses increased [ 45 ]. There was also an apparent
increase in the number of detectable pulses during the 8-h infusion period, but it is
unclear whether this observation was due to an increase in pulse frequency of the
GnRH pulse generator or secondary to the increase in pulse amplitude, such that
previously undetectable pulses could now be detected.
These results demonstrated that GnRH neurons are present in patients with muta-
tions affecting neurokinin B signaling and that kisspeptin does not require neuroki-
nin B signaling for its ability to enhance GnRH secretion, consistent with the model
that neurokinin B acts through kisspeptin to stimulate GnRH release [ 49 ]. However,
neurokinin B may also have effects independent of kisspeptin—though kisspeptin
enhanced LH pulse amplitude in patients with TAC3 and TACR3 mutations, this
enhancement was not as pronounced as what had been observed in healthy adults.
This study scratches the surface of potential uses of kisspeptin in patients with
isolated GnRH defi ciency. Kisspeptin will undoubtedly be used in future studies to
further probe the pathophysiology of isolated GnRH defi ciency, to establish an earlier
diagnosis, and possibly to predict later outcomes such as success at achieving fertility.
Kisspeptin also has the potential for treating patients with isolated GnRH defi ciency
who retain responsiveness to kisspeptin. The recent identifi cation of patients with
homozygous deleterious mutations in KISS1 , the gene that encodes kisspeptin [ 50 ],
may permit detailed studies of the physiological effects of kisspeptin in a “clean”
model of kisspeptin defi ciency, much as patients with GnRH defi ciency have offered
a valuable opportunity to characterize the pituitary response to GnRH [ 51 ].
An Extended Duration of GnRH Secretion Induced by Kisspeptin
The above studies have demonstrated the general principle that kisspeptin induces
LH secretion, a surrogate marker of GnRH secretion, in humans. Further insight
into the effects of kisspeptin on GnRH secretion came from examining the shape of
the LH pulses induced by kisspeptin [ 11 ]. Unlike endogenous LH pulses, which
have a triangular, sawtooth appearance with a rapid rise and subsequent peaking of
LH, the LH pulses induced by exogenous kisspeptin-10 were more rounded and
slower to reach their peaks [ 11 ]. A similar rounded, prolonged morphology of LH
pulses was seen in a prior study in which exogenous GnRH infusions were delivered
for varying lengths of time (from an IV push to 1-, 5-, and 30-min infusions) [ 52 ].
These studies were performed in men with GnRH defi ciency to eliminate any con-
founding effects of endogenous GnRH secretion. As the length of the GnRH infusion
increased, the resulting LH pulses appeared more rounded and had a longer time
from the nadir to the peak of the pulse (Fig. 5.2 ). This time-to-peak was directly
proportional to the duration of the GnRH infusion (Fig. 5.2 ). Placing the time-to-peak
of LH pulses induced by kisspeptin-10 in the context of this prior study suggested
that the morphology of the kisspeptin-induced LH pulses could be mimicked by a
17-min infusion of GnRH (Fig. 5.2 ).