Sex Steroid Regulation of Kisspeptin Circuits - Kisspeptin Signaling in Reproductive Biology - page 269

Introduction: First Kiss

Not since the discovery of gonadotropin-releasing hormone (GnRH) has a neuro-
peptide created such a stir of activity within the fi eld of reproduction. Kisspeptin
research has been rapid and momentous, and it is undeniable that this peptide is
critical for many neuroendocrine aspects of fertility (as indicated in this textbook).
The neuroendocrine reproductive axis is governed through meticulously controlled
neural and hormonal interactions between the brain, pituitary, and gonads. In the
brain, the fi nal common factor in the control of this hierarchical system is the
release of GnRH from neurons extending to the median eminence. GnRH stimu-
lates the pituitary gonadotropes and leads the production of gonadal sex steroids
(androgens, estrogens, and progestins), which then “feedback” to GnRH neurons to
control their activity [ 1 ]. In males and females, testosterone, estradiol, and proges-
terone act via tonic negative feedback to suppress GnRH secretion, which is neces-
sary for optimal steroidogenesis and gametogenesis. In females, there is an
additional switch from negative feedback to acute estrogen positive feedback,
which precedes and causes the GnRH/LH surge, necessary for ovulation. Although
GnRH was discovered more than 30 years ago, the precise cellular and molecular
mechanisms governing sex steroid negative and positive feedback on GnRH secre-
tion have proved far more challenging to uncover. GnRH neurons do not express
androgen receptor, estrogen receptor

), or progesterone receptor (PR) [ 2 - 4 ];
thus, the feedback effects of sex steroids on GnRH secretion must be transferred by
other steroid-sensitive neurons. Enter kisspeptins.
Produced from the Kiss1 gene, kisspeptin peptides are robust stimulators of
GnRH secretion [ 5 ]. Evidence for this now includes (1) the stimulatory effect of
kisspeptin on gonadotropin secretion is blocked by GnRH antagonists [ 5 - 8 ]; (2)
injections of kisspeptin directly in to the preoptic area (POA), where GnRH neurons
reside, stimulate LH secretion [ 9 ]; (3) kisspeptin activates (as determined by fos
induction) GnRH neurons [ 6 , 7 ]; (4) kisspeptin directly stimulates the electrophysi-
ological properties of GnRH neurons [ 10 , 11 ]; (5) kisspeptin-immunoreactive fi bers
appose GnRH neurons [ 12 - 14 ]; (6) kisspeptin stimulates GnRH release into the
portal circulation of sheep [ 15 ]; and (7) almost all GnRH neurons express the kiss-
peptin receptor (Kiss1r) [ 6 , 10 , 16 ]. Importantly, the effects of kisspeptin are absent
in Kiss1r knockout mice, showing specifi city to this receptor [ 17 - 19 ].

α (ER α

First Clues: Kiss1 Distribution and Kisspeptin Projections

Discrete localization of Kiss1 mRNA in the brain was fi rst determined in the mouse
by in situ hybridization and immediately provided clues to the physiological role of
kisspeptin. Cellular populations were identifi ed primarily in the anteroventral peri-
ventricular nucleus (AVPV), extending to periventricular nucleus (PEN), and the
arcuate nucleus (ARC) [ 5 ]. Smaller, less dense populations of Kiss1 -expressing