Effects of Kisspeptin on Hormone Secretion in Humans - Kisspeptin Signaling in Reproductive Biology - page 91

In summary, though some details remain to be worked out regarding the pharma-
cokinetics of the various isoforms of kisspeptin, it is clear that kisspeptin-10 decays
very rapidly, kisspeptin-54 less so. Furthermore, as with most drugs, subcutaneous
dosing results in more sustained elevation of kisspeptin immunoreactivity than
intravenous administration. These pharmacokinetic studies are an important back-
drop to the interpretation of studies of human kisspeptin administration. In particu-
lar, the fi nding that subcutaneous administration of kisspeptin-54 at high doses
results in sustained elevation of kisspeptin immunoreactivity is important for the
interpretation of the studies involving multiple subcutaneous doses of this isoform
(described below in section “ Effects of Chronic Kisspeptin Administration in
Women with Hypothalamic Amenorrhea ”).
Stimulation of Reproductive Endocrine Activity by Acute
Administration of Kisspeptin
Shortly after the fi nding that mutations in KISS1R / Kiss1r cause hypogonadotropic
hypogonadism in humans and mice, several studies demonstrated that kisspeptin
potently and directly stimulates GnRH secretion and, in turn, gonadotropin secretion
[ 16 - 19 ]. A number of studies have now shown that kisspeptin similarly stimulates
gonadotropin secretion in humans and have further extended these fi ndings to reveal
previously unrecognized aspects of kisspeptin physiology. The results of studies of
human kisspeptin administration are summarized in Table 5.2 .
These human studies all share certain limitations. One is that it is nearly impossi-
ble to measure hypothalamic GnRH secretion directly in humans. All studies have
therefore used LH as an indicator of GnRH secretion, as LH pulses are a well-validated
surrogate measure of GnRH secretion under physiologic conditions [ 20 , 21 ]. However,
LH becomes less reliable under non-physiologic conditions. For example, when
exogenous pulsatile GnRH is given at a high pulse frequency (every 30 min or faster),
the one-to-one concordance between GnRH pulses and LH pulses begins to break
down [ 22 ]. In these situations, other markers such as the free alpha subunit more
accurately refl ect GnRH secretion [ 23 ], but to date measurements of the free alpha
subunit have not been included in human studies of kisspeptin. Human kisspeptin
studies have also measured FSH and testosterone in men or estradiol in women, and
these have generally changed in parallel with LH; this chapter will focus on the LH
response to kisspeptin, as this most closely correlates with GnRH secretion.
To date, most human studies have been performed in reproductively normal
adults. These healthy subjects have normal endogenous secretion of kisspeptin,
GnRH, and LH, and this endogenous reproductive endocrine activity complicates
the interpretation of studies involving exogenous kisspeptin administration. In par-
ticular, the unpredictable timing of endogenous pulses of GnRH and LH secretion
results in a constantly moving baseline that can confound the interpretation of LH
measurements after kisspeptin administration. This is illustrated by the observation
in several studies (e.g., [ 14 , 15 , 24 ]) that mean LH often decreases after subjects