Kisspeptin and GnRH Pulse Generation - Kisspeptin Signaling in Reproductive Biology - page 291

Discovery of Gonadotropin-Releasing Hormone
Pulses and Surges
There is little doubt that the pulsatile nature of pituitary LH secretion is caused by
the pulsatile release of GnRH from nerve terminals located in the median eminence,
because GnRH is considered to be the single hypothalamic releasing factor stimu-
lating pituitary LH secretion. Initially, however, this was only a belief and not based
on solid evidence. The pulsatile nature of GnRH secretion was fi rst seen in 1982 in
a landmark study by Clarke and Cummins [ 15 ] and later examined in greater detail
by Moenter et al. in the early 1990s. Both groups used a skillful technique of portal
cannulation in sheep and very frequent portal blood collections (e.g., 30-s inter-
vals!) to demonstrate beautiful GnRH pulses, each of which corresponded to simul-
taneous LH pulses [ 16 ]. The width of GnRH pulses was found to be narrower than
LH pulses, suggesting that the half-life of GnRH in the portal blood is much shorter
than the half-life of LH in the peripheral circulation [ 16 ]. This pioneering work
demonstrated the clear relationship between GnRH and LH secretion, and sup-
ported the earlier studies by Knobil's group demonstrating that when pulses of
GnRH were infused to monkeys bearing hypothalamic lesions and abolished pulsa-
tile LH secretion, LH secretion was restored in a pulsatile fashion, with each LH
pulse corresponding beautifully to each experimental GnRH pulse [ 17 ]. Additionally,
artifi cial pulsatile infusion of GnRH, with 1-h intervals, stimulated the ovary to
produce complete menstrual cycles [ 3 ], whereas monkeys exposed to less frequent
GnRH pulses showed no sign of ovarian activity [ 18 ].
In addition to identifying GnRH pulses in their sheep portal samples, Moenter
et al. also observed robust periodic GnRH surges [ 19 ]. The discovery of GnRH
surges leads to a dramatic turnaround in the theory of the LH surge formation,
because researchers had previously believed that a high frequency of LH pulses
during the preovulatory period caused a surge. This model held that when the
frequency of LH pulses was too high to be effectively cleared from the circulation,
the blood LH concentration would not decline and would keep increasing (i.e., a
surge) until pulse frequency eventually drops. However, this idea was rejected after
the discovery that a huge amount of GnRH is released just prior to LH surges, and
the GnRH surge release continues even after the end of LH surges [ 19 ]. Currently,
researchers believe that the GnRH and LH surges are generated by a mechanism
different from that generating GnRH/LH pulses.
Anatomical Location of the GnRH Pulse Generator
The anatomical location of the GnRH pulse-generating mechanism has always been
a big puzzle for reproductive endocrinologists. The fi rst work describing the possi-
ble location of the center for pulsatile GnRH secretion was conducted by Halasz and
Pupp [ 20 ], who utilized a micro “Halasz” knife in rats to isolate specifi c brain