Biology Reference
In-Depth Information
Introduction
There are two modes of gonadotropin-releasing hormone (GnRH) and luteinizing
hormone (LH) secretion: one mode is the surge, necessary for ovulation in females,
and the other is the pulse, required for the tonic support of reproductive function in
both sexes. For example, GnRH pulses are needed to initiate the process of repro-
ductive cycles, such as estrous cycles, in females. Follicular development is stimu-
lated by the increase in frequency of GnRH/LH pulses, resulting in a surge-like
secretion of estrogen from the mature follicles. The increased estrogen acts in the
brain to cause the GnRH surge to induce ovulation in females. In contrast, males do
not generate GnRH surges, and therefore only have the pulse mode of GnRH secre-
tion, to maintain testicular activities such as spermatogenesis and steroidogenesis.
Therefore, manipulation of the activity of the GnRH pulse generator is of therapeu-
tic potential in both sexes, and the GnRH pulse generator is a good target for the
development of drugs that might control fertility. This chapter focuses on the
involvement of kisspeptin, and other related peptides, in the generation of GnRH
pulses in mammals.
Discovery of Pulsatile LH Secretion
Pulsatile secretion of LH was fi rst described, in monkeys, in 1970 by Knobil [
1
].
This was only a few years after the establishment of a radioimmunoassay for LH in
the blood [
2
]. Knobil had noticed that the concentration of LH in the blood fl uctu-
ated signifi cantly from assay to assay, or from time to time, in monkeys. He then
utilized frequent blood collections in monkeys to determine the cause of these fl uc-
tuations. The resultant data exposed a beautiful series of plasma LH concentrations
displaying repetitive abrupt increases in LH followed by an exponential decrease,
the distinguishing feature of pulses [
1
].
The discovery of LH pulses changed the concept of hormone actions, because
gonadal activity was subsequently shown in rhesus macaques to be controlled by
the “frequency” of LH pulses [
3
-
5
]. The greater the LH pulse frequency, the greater
the resultant gonadal activity. Knobil's experiments elegantly proved that gonadal
activity is completely dependent on the pulse frequency of LH release. After the
discovery of pulsatile LH secretion in monkeys, reproductive endocrinologists
began to reveal the pulsatile nature of LH secretion in various other mammalian
species, including rats [
6
], sheep [
7
], cows [
8
], pigs [
9
], and horses [
10
], although
frequent blood sampling was sometimes diffi cult in some species under no anesthesia
and freely moving conditions. These data reiterated the importance of LH pulse
frequency for the regulation of gonadal activities. Consistent across species, more
frequent LH pulses are found during the follicular phase, whereas the pulse frequency
is lower during luteal phase [
8
,
11
,
12
]. In seasonal animals, such as sheep, LH
pulses are more frequent during the breeding season and less frequent in the nonbreeding
season [
13
]. Interestingly, the frequency of the pulse is negatively correlated with
the size of the body [
14
].
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