Biology Reference
In-Depth Information
Gonadotropin Responses to NKB
The initial characterization of the action of NKB upon gonadotropin release has
been controversial. The fi rst studies documented null, or even inhibitory, actions of
NKB or the selective NK3R agonist, senktide, on LH release. A study by Sandoval-
Guzmán and Rance showed that ovariectomized and estradiol-replaced rats exhib-
ited a substantial decrease in circulating LH levels after senktide treatment [
74
]. To
note, these animals failed to display the expected phenotype subsequent to estradiol
replacement, i.e., lowering of the postcastration rise of LH, and, therefore, they
should be considered as ovariectomized and sham-replaced animals. In the same
vein, the latter rationale could also apply to a recent study by Kinsey-Jones et al.
[
79
]. As a consequence, considering this limitation, the above observations would
essentially be in keeping with previous reports documenting inhibitory actions of
senktide (or NKB) in gonadectomized mice, rats, and goats [
22
,
56
,
76
]. These
results, in fact, were clearly contradictory to the initially predicted stimulation of
LH release by NKB on the basis of the human studies, in which patients suffering
constitutive defi ciency in the NKB system exhibited hypogonadotropic hypogonad-
ism [
6
,
8
-
10
,
13
]. Interestingly, this defi ciency in humans seemed to be exclusively
restricted to LH release, since FSH levels appeared relatively normal [
8
]. This fea-
ture of NKB-null patients suggests a residual low-frequency release of GnRH
(NKB-independent), which may result as a consequence of the action of high vs.
low pulses of GnRH in the discrimination of LH or FSH release, respectively [
80
,
81
]. Despite the above observations, the overall literature on this topic substantiates
a remarkable discrepancy in the response to NKB or senktide in different physiolog-
ical settings. However, a growing number of studies are offering irrefutable demon-
strations of the robust stimulatory action of NKB upon gonadotropin release in a
number of species [
22
,
31
,
40
,
43
,
59
,
76
,
82
,
83
]. In this sense, while further inves-
tigation is needed to fully understand this paradox (stimulation or inhibition of LH
release after senktide treatment), studies in gonadectomized and sham-replaced vs.
E
2
-replaced animals strongly suggest the need of physiological levels of circulating
sex steroids (acting on ER
, most likely, in KNDy neurons) to allow the stimulation
of LH release by NKB. This is also in line with the stimulatory action of senktide
on LH secretion in the follicular, but not luteal, phase in sheep [
43
]. Of note, con-
tinuous stimulation of NK3R with senktide leads to desensitization of the receptor
[
83
], which might, hypothetically, imply that under the elevated levels of kisspeptin
and NKB reached in gonadectomized animals, the additional stimulation of NK3R
by senktide could account for the observed decrease of LH release in E
2
-deprived
animals. Admittedly, a recent publication indicates that, in this scenario, dynorphin
may be hyperstimulated by senktide and, consequently, mediate this inhibition [
79
].
This inhibitory action, however, remains to be carefully explored.
Notwithstanding the important role of NKB upon GnRH release, NKB's charac-
terization initially focused on the female. Intriguingly, subsequent studies in the
male are now suggesting a more complex regulation of the NKB system than previ-
ously anticipated. In this sense, initial studies in male mice pointed to a likely sexual
α
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