Stress Regulation of Kisspeptin in the Modulation of Reproductive Function - Kisspeptin Signaling in Reproductive Biology - page 432

Mechanisms Integrating Stress Networks
and Kisspeptin Signaling
Despite many similarities in which various stressors activate the HPA axis and/or
the sympathetic nervous system, as well as inhibit the HPG axis, a number of dis-
parities are also evident from current literature. First, the central mediators of the
stress response are differentially implicated in the suppression of the GnRH pulse
generator. Consistent with a CRF-dependent mechanism of stress suppression of the
HPG axis are the fi ndings that, in the female rat, (1) icv administration of CRF [ 38 ]
or a selective CRF-R2 agonist [ 39 ] prolongs the LH pulse interval; (2) CRF-R2
antagonism blocks the suppression of pulsatile LH secretion induced by restraint
[ 39 ], insulin-induced hypoglycemia, and LPS [ 40 ]; and (3) the inhibitory effect of
restraint stress on LH secretion is blocked by a selective CRF-R1 antagonist [ 40 ].
However, blockade of CRF-R1 did not affect the hypoglycemia- and LPS-induced
suppression of the GnRH pulse generator [ 40 ]. Furthermore, while CRF, insulin-
induced hypoglycemia, and LPS downregulated the expression of both kisspeptin
and its receptor in the ARC and mPOA, restraint did not affect the ARC expression
of Kiss1r [ 35 ]. These fi ndings point at the notion that different stressors employ dif-
ferential neural mechanisms for the activation of the stress response and suppres-
sion of the reproductive axis.
Second, while various stress paradigms, as well as icv CRF administration, potently
downregulate Kiss1 and Kiss1r mRNA expression in the ARC and mPOA, concomi-
tant with suppression of pulsatile LH secretion, both acute and chronic administration
of physiological CORT downregulate Kiss1 , but upregulate Kiss1r expression, with
no net effect on LH pulses [ 35 ]. Indeed, acute stress-induced CORT release has no
effect on pulsatile LH secretion in the monkey [ 88 ]. Further, treatment with metyra-
pone, an inhibitor of adrenal steroidogenesis that prevented the CRF-induced rise in
CORT levels, did not reverse the inhibitory effects of CRF on GnRH pulse generator
frequency in the rhesus monkey [ 89 ]. The decrease in the ARC expression of Kiss1
mRNA following CORT administration has also been shown in male mice, and CORT
was hypothesized to infl uence kisspeptin neurons directly, in light of the expression of
glucocorticoid receptors (GR) by these cells [ 36 ], despite previous reports that gonadal
GR mediate the stress-induced CORT feedback on the HPG axis [ 90 ]. In mice, how-
ever, CORT did decrease LH levels, albeit at a pharmacological dose [ 36 ]. Kisspeptin,
on the other hand, affects neither CORT nor adrenocorticotropin hormone (ACTH)
levels under basal or restraint stress conditions, in adult male rats [ 53 ]. It is apparent,
therefore, that central and peripheral processes of the HPA axis modulate hypotha-
lamic kisspeptin signaling in different ways. It is important to note that components of
the stress axis do not act in isolation in vivo, and hence multiple parameters of the
stress response need to be considered when extrapolating conclusions regarding the
stress feedback to the kisspeptin/Kiss1r system.
Third, different neuronal populations appear to mediate the suppressive effects of
different types of stress. In addition to the aforementioned involvement of CRF-R1 and
CRF-R2 in the suppression of pulsatile LH secretion under various stress paradigms,