Effects of Kisspeptin on Hormone Secretion in Humans - Kisspeptin Signaling in Reproductive Biology - page 87

essential for stimulating normal GnRH secretion, and that these kisspeptin neurons
integrate multiple inputs (developmental changes, sex steroids, metabolic status,
stress, photoperiod, etc.) and relay these inputs to GnRH neurons. Though there have
been only a relatively small number of studies of the effects of kisspeptin in humans,
these studies have added to work in animal models to enhance our knowledge of
kisspeptin physiology.
Studies in the human can be challenging to execute and are constrained by safety,
ethical, and regulatory issues, but these diffi culties are offset by distinct advantages of
the human model. One obvious advantage is that only human studies can provide
defi nitive information about the human physiology of kisspeptin, as well as the safety
of kisspeptin in humans. Another advantage is that human subjects can cooperate with
complex dosing regimens, such as repetitive injections and prolonged infusions, and
can also self-administer medications. A third advantage is the ability to perform fre-
quent blood sampling for extended periods of time, allowing detailed characterization
of endogenous reproductive endocrine activity at baseline, which serves as an impor-
tant reference point to which responses to exogenous kisspeptin can be compared.
Pharmacokinetics of Kisspeptin in Humans
Human studies involving kisspeptin administration have used different isoforms of
kisspeptin (kisspeptin-54 and kisspeptin-10), different routes of administration (intra-
venous and subcutaneous), and different modes of administration (single boluses,
multiple boluses, and infusions of varying duration). These multiple variables compli-
cate comparisons between studies. Fortunately, it appears that differences in the
effects of these various kisspeptin isoforms and routes and modes of administration
can largely be explained by differences in pharmacokinetics—that is, how quickly
kisspeptin accumulates after administration and how quickly it subsequently degrades.
Kisspeptin-10 and kisspeptin-54, when applied directly to cultured cells in vitro, have
similar activity and potency [ 4 - 6 ]. In contrast, in vivo experiments in rodents have
demonstrated that kisspeptin-54 has a slightly longer onset and duration of action than
kisspeptin-10 when given at the same molar concentration and by the same route
[ 7 , 8 ]. Because the two isoforms have essentially identical activity in vitro, these
in vivo differences are likely to be due to differences in kisspeptin pharmacokinetics.
Thus, understanding the pharmacokinetics of the various kisspeptin isoforms
and routes of administration in humans is vital for proper interpretation of the results
of studies of kisspeptin administration in humans. However, the seemingly straight-
forward task of determining the pharmacokinetics of kisspeptin has proved to be
challenging, due both to limitations of existing assays for measurement of kisspeptin
and to gaps in our knowledge of the metabolism and degradation of kisspeptin.
Thus, while several studies have examined the pharmacokinetics of kisspeptin
(summarized in Table 5.1 ), our understanding remains incomplete. Nevertheless,
these studies provide an essential backdrop for the interpretation of studies of
kisspeptin administration to humans.