Effects of Kisspeptin on Hormone Secretion in Humans - Kisspeptin Signaling in Reproductive Biology - page 100

Fig. 5.2 Sustained GnRH secretion induced by kisspeptin-10 in men. ( a ) Men with GnRH defi -
ciency received GnRH as an intravenous bolus or as 1-, 5-, or 30-min intravenous infusions, result-
ing in increasingly prolonged LH pulses, with a longer time from the nadir to the peak of the pulse.
Healthy men received kisspeptin-10 as an intravenous bolus ( shaded graph ). ( b ) The relationship
between the length of the GnRH infusion and the time from the nadir to the peak of the resulting
LH pulse is linear. When plotted on this graph, the average time from nadir to peak of kisspeptin-
induced LH pulses (28 min) corresponds to a 17-min GnRH infusion. Adapted with permission
from ref. [ 11 ]
Thus, a single IV dose of kisspeptin-10 appears to induce prolonged GnRH
secretion. One potential explanation for this is that exogenous kisspeptin-10 could
persist for an extended time in the circulation. However, as noted in section
“ Pharmacokinetics of Kisspeptin-10 ,” the half-life of kisspeptin-10 is very short,
making this possibility unlikely. Another possibility is that brief exposure of hypo-
thalamic GnRH neurons to kisspeptin induces prolonged GnRH release. Indeed, in
several studies of cultured GnRH neurons in which kisspeptin was applied briefl y
then washed away, the GnRH neurons exhibited prolonged electrochemical activation
and calcium mobilization [ 53 - 57 ]. In one study, the average duration of this activa-
tion was 16 min [ 56 ], remarkably concordant with the estimate of 17 min of GnRH
secretion induced by kisspeptin-10 in humans. Thus, the morphology of the LH
pulses induced by kisspeptin in vivo revealed an important in vivo human correlate
of a phenomenon observed in ex vivo mouse studies.
Effects of Kisspeptin on GnRH Pulse Generation
The mechanism by which GnRH neurons produce periodic pulses of GnRH secre-
tion remains one of the key mysteries of reproductive neuroendocrinology [ 58 ].
How these pulses are generated and how the timing of pulses is determined are
largely unknown. Indeed, whether the “pulse generator” physically resides within
the GnRH neuronal network or in some other anatomic location has been a topic of
lively discussion [ 59 ]. One diffi culty in studying GnRH pulse generation has been a
relative dearth of tools to study this phenomenon. While progesterone, acting
through endogenous opioids, is known to cause a chronic slowing of the frequency
of GnRH pulses [ 60 ], there had not been a factor known to acutely perturb the
pattern of GnRH pulse generation. Human studies of kisspeptin have now revealed
that kisspeptin may be such a factor.