Sex Steroid Regulation of Kisspeptin Circuits - Kisspeptin Signaling in Reproductive Biology - page 282

Fig. 13.6 Schematic diagram demonstrating the likely pathways resulting in differential regula-
tion of Kiss1 in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) of
female mice. In the AVPV, the stimulation of Kiss1 is likely to occur through classical and not
nonclassical signaling pathways. Conversely, in the ARC, the inhibition of Kiss1 mRNA is medi-
ated by a nonclassical ERE-independent ER signaling mechanism possibly involving interactions

with transcription factors (TF)—nonclassical estrogen signaling [ 5 ]

α

This is consistent with a report showing the positive feedback effects of estradiol
require classical signaling, whereas negative feedback involves nonclassical signaling
mechanisms [ 85 ].

Sex Steroid Regulation of Kisspeptin Sensitivity

It is clear that kisspeptin “output” from specifi c hypothalamic nuclei is increased at
the time of the preovulatory GnRH/LH surge. In addition to this, the sensitivity of the
hypothalamic-pituitary-gonadal axis to kisspeptin varies across different reproduc-
tive states. In humans, the LH response to kisspeptin treatment appears to be highest
during the preovulatory phase of the menstrual cycle in women [ 86 ], with similar data
in sheep [ 15 , 87 ] and rats [ 88 ]. At face value, these data suggest that the GnRH/LH
surge is stimulated by kisspeptin in a “two-step mechanism” consisting of increased
kisspeptin output from the hypothalamus and increased kisspeptin sensitivity at the
GnRH neuron. Moreover, these data support a role for sex steroids in the modulation
of LH responses to kisspeptin. In rats, maximal LH and FSH responses to kisspeptin
require replacement of estradiol and progesterone in an OVX model [ 88 ]. In terms of
estrogen action, subsequent studies indicate the LH response to kisspeptin is modu-
lated by ER

, with blockade in female rats blunting the LH response, which could
alternatively be increased after selective activation of ER

α

α [ 89 ]. In contrast, antago-

nism of ER β augmented acute LH responses to kisspeptin [ 89 ]. Alternatively, antago-

nism of ER equally blunted the FSH response to kisspeptin [ 90 ].

Any effects of sex steroids on the gonadotropin response to kisspeptin are likely
to be mediated by effects on Kiss1r expression on GnRH neurons. Data demonstrating

α or ER β