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changes in both the basal and stress-induced activity of the HPA axis. Generally,
these facets have been interpreted as refl ecting the chronic stress of social
subordinance.
Social status is important in determining reproductive function in addition to
stress reactivity in a wide variety of species. The common marmoset is a well-
studied primate model of socially mediated infertility, in which subordinate
females display impaired hypothalamic GnRH secretion and anovulation [
78
],
and receipt of aggression from female conspecifi cs reduces LH pulse frequency
[
79
]. The role of kisspeptin signaling in socially induced infertility in the common
marmoset or other primates has not been reported. However, subordination in
other species, including the naked mole rat, which exhibit extreme socially
induced suppression of the HPG axis [
80
] displays downregulated kisspeptin in
the AVPV [
81
]. Similarly, in the teleost fi sh,
Astatotilapia burtoni
, reduced
Kiss1r
expression was observed in whole brain of reproductively suppressed subordinate
males [
82
].
Naturally, there are many caveats in extrapolating these data to humans.
Nevertheless, it is of note that about 35% of women presenting with secondary
amenorrhea are diagnosed with functional hypothalamic amenorrhea. In these
women, effective stress management results in reversal of the extant low LH pulse
frequency and hypercortisolism, and restoration of fertility in the vast majority [
83
].
The cynomolgus monkey has proved an exquisite primate model of functional
hypothalamic amenorrhea, in which CRF-R1 antagonism restores normal GnRH
pulse generator frequency suppressed by a combination of mild psychosocial and
metabolic stressors that simulate the stressor indices of functional hypothalamic
amenorrhea in women [
84
,
85
]. Although the role of kisspeptin signaling has not
been examined in this primate model, intermittent kisspeptin administration stimu-
lates gonadotropin release in women with hypothalamic amenorrhea [
86
].
Furthermore, continuous kisspeptin infusion restores pulsatile LH secretion in men
with hypogonadotropic hypogonadism resulting from loss-of-function mutations in
NKB ligand and receptor [
87
].
A vast body of literature supports the notion that the GnRH pulse generator, as
well as other reproductive networks within which kisspeptin signaling plays a key
role, is exquisitely sensitive to changes within the environment, either as a direct
consequence of perceived stressful stimuli or through autonomic suppression of
nonessential physiological processes. Kisspeptin has widely been dubbed a central
gatekeeper of reproductive function; however, such a moniker does not adequately
befi t the suitor in the context of stress suppression of the HPG axis. Expression of
Kisspeptin and/or its receptor is downregulated by a variety of stressors and media-
tors of the stress response, “surrendering” gracelessly at the mere sight of “intrud-
ers” and thus allowing the instillation of a suppressive “regime.” It is perhaps this
submissive nature of the kisspeptin/Kiss1r system that allows stressful stimuli to
deregulate reproductive processes and, in some individuals, lets this develop into
reproductive pathologies. To consolidate the grounds for an interaction between
kisspeptin signaling and the stress response, we proceed to reviewing recent data
that suggest potential neural mechanisms for this interaction.
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