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suppression of reproductive endocrine activity by stress, excessive exercise, and/or
negative energy balance [ 39 ]. In rodent models, starvation and stress also suppress
reproductive endocrine activity, and this is associated with a decrease in kisspeptin
expression in the arcuate nucleus of the hypothalamus [ 40 - 42 ]. In stressed/starved
rodents, kisspeptin can still elicit LH secretion [ 40 , 41 ], demonstrating that path-
ways downstream of the kisspeptin receptor remain intact under these conditions.
These results indicate that, at least in some situations, stress inhibits reproductive
endocrine activity by suppressing kisspeptin release.
It is therefore logical to postulate that restoring kisspeptin would rescue the
reproductive defi cits induced by stress/starvation. To test this possibility, Jayasena
et al. administered kisspeptin to women with HA [ 43 ]. The researchers found that
single subcutaneous boluses of kisspeptin-54 at a dose of 6.4 nmol/kg caused sig-
nifi cant elevations in LH, FSH, and estradiol. This important proof of principle
demonstrated that pathways downstream from kisspeptin remain intact in women
with HA. This group's efforts to restore reproductive endocrine activity to women
with HA by chronic treatment with kisspeptin are described below in section
Effects of Chronic Kisspeptin Administration in Women with Hypothalamic
Amenorrhea .”
Effects of Kisspeptin in Patients with GnRH Defi ciency
Individuals who are unable to secrete or respond to GnRH have a condition
variously termed idiopathic/congenital hypogonadotropic hypogonadism or
idiopathic/congenital GnRH defi ciency [ 44 ]. These individuals fail to go through
puberty and are infertile. The past 15 years have seen important advances in our
understanding of the genetics of isolated GnRH defi ciency [ 44 ], and two basic patho-
physiological mechanisms for this condition have emerged. “Neurodevelopmental”
defects result from a problem in the development and/or migration of the GnRH
neurons, such that GnRH neurons are absent or present in reduced number in the
central nervous system. In contrast, individuals with a “neuroendocrine” defect have
a normal complement of GnRH neurons, but these neurons fail to receive the signals
to induce GnRH secretion, they are unable to produce functional GnRH, or the pitu-
itary gland is unable to respond to GnRH [ 44 ]. Though these two pathophysiological
mechanisms are largely distinct, they can produce virtually identical phenotypes in
patients. Because kisspeptin directly stimulates GnRH secretion, it can be used as
the fi rst available in vivo probe of GnRH neuronal integrity, just as GnRH has been
used for decades to probe pituitary gonadotrope function [ 34 ].
To date, one study has examined the effects of kisspeptin-10 in patients with
GnRH defi ciency [ 45 ]. This study administered 8-h infusions of kisspeptin to
patients with mutations in TAC3 or TACR3 , which encode neurokinin B and its
receptor, respectively [ 45 ]. These genes fall in the “neuroendocrine” class of genes,
as neurokinin B signaling is thought to directly or indirectly modulate the secretion
of GnRH neurons [ 46 - 48 ]. When given a control infusion with saline, these patients
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