Effects of Kisspeptin on Hormone Secretion in Humans - Kisspeptin Signaling in Reproductive Biology - page 96

in the circulation. In both of these studies, kisspeptin-10 induced robust LH secretion
in women in the late follicular phase of the menstrual cycle (Fig. 5.1 ), in the days
before ovulation when pituitary sensitivity to GnRH is greatly enhanced due to
positive estradiol feedback [ 30 ]. One study also showed that women in the mid-
luteal phase exhibit robust LH responses to kisspeptin (Fig. 5.1 ), though not as large
as in preovulatory women [ 31 ].
In contrast, markedly attenuated responses to kisspeptin were seen in the early to
mid-follicular phase (Fig. 5.1 ), the time in the menstrual cycle when circulating
estradiol concentrations are lowest [ 30 ]. In one study, no signifi cant increases in LH
were seen in women in the early to mid-follicular phase after administration of
kisspeptin-10 as single intravenous boluses (1-10 nmol/kg), or even as single sub-
cutaneous boluses (2-32 nmol/kg) or 90-min intravenous infusions (cumulative
doses 1.2-43.2 nmol/kg) [ 14 ]. In the other study, LH increases could be detected in
the early follicular phase, but the responses were both small and inconsistent, with
immediate LH pulses seen in only half of subjects [ 31 ].
The effects of slightly more sustained exposure to kisspeptin were examined by
delivering single intravenous boluses of the 54-amino acid isoform of kisspeptin to
women in the early to mid-follicular phase [ 14 ]. As described in section
“ Pharmacokinetics of Kisspeptin-10 ,” this results in sustained elevation of kiss-
peptin immunoreactivity, and the gonadotropin response to kisspeptin-54 was simi-
larly sustained: LH rose gradually across the study and did not reach a plateau by
the end of the 3-h study period.
The effects in women of even more prolonged exposure to kisspeptin have been
examined using the subcutaneous route of administration for kisspeptin-54 [ 15 ].
Because subcutaneous administration of kisspeptin-54 behaves as a sustained release
formulation of kisspeptin, these studies explored the gonadotropin response to pro-
longed kisspeptin exposure. In women in the early to mid-follicular phase, single
subcutaneous doses of kisspeptin-54, ranging from 0.2 to 6.4 nmol/kg, resulted in
dose-dependent increases in LH and FSH [ 15 ]. The 0.4 nmol/kg dose was further
studied in women in different phases of the menstrual cycle: early to mid-follicular,
late follicular/preovulatory, and mid-luteal. Mirroring the results with kisspeptin-10,
the largest gonadotropin responses were seen in the preovulatory period (LH increase
~20 IU/L peaking 60 min after injection). In the early follicular phase, the gonado-
tropin responses to kisspeptin-54 were much smaller and were also relatively delayed
(LH increase ~1 IU/L peaking at 150 min after injection).
Women in the mid-luteal phase exhibited a biphasic response to subcutaneous
kisspeptin-54 0.4 nmol/kg, with an initial peak 30-45 min after injection (~2 IU/L
above baseline) and a second, larger peak 180-210 min after injection (~4 IU/L
above baseline). An identical biphasic response had been observed with extended
infusions of GnRH [ 32 ] and administration of long-acting GnRH analogs [ 33 ].
Thus, the biphasic LH response to sustained exposure to kisspeptin can be attributed
to the behavior of the pituitary gonadotropes in response to sustained activation of
the GnRH receptor.
Comparing kisspeptin-induced pulses to endogenous pulses, the size (AUC) of
pulses induced by kisspeptin-10 0.24 nmol/kg IV was greater than that of endogenous