Biology Reference
In-Depth Information
Future Applications in Physiological Regulation
of Gonadotropins
To date, few studies have examined the effects of KP antagonists on FSH secretion.
Although both LH and FSH secretion are dependent on GnRH, low GnRH pulse
frequencies favour FSH secretion while high pulse frequencies favour LH secretion
[ 36 ]. Since KP antagonists slow LH pulse frequencies (and by inference, GnRH
pulse frequency) in a number of the models studied, it may be instructive to study
the effects on FSH secretion.
Leptin stimulates Kiss1 gene expression and increases gonadotropins in leptin-
defi cient and nutritionally deprived mice [ 37 ]. Studies on the ability of KP antago-
nists to inhibit leptin stimulation of gonadotropin in these models would provide
direct evidence for leptin stimulation of gonadotropin through stimulation of KP
secretion. KP antagonists could also be employed to interrogate other metabolic
stimulators of gonadotropins. Another area which has yet to be investigated is the
effect of gonadal peptides (inhibin, activin, and follistatin) on the KP system.
Conversely, KP antagonists can be used to investigate the potential role of basal
gonadotropin secretion on the production of these gonadal peptides.
KP, neurokinin B (NKB), and dynorphin (Dyn) are co-expressed by a population
of neurons in the ARC of sheep [ 38 , 39 ], goats [ 40 ], rodents, and humans [ 41 ], and
a model is emerging that involves a complex dialogue between these peptide hor-
mones and their effects on the GnRH neuron. Putative paracrine and autocrine feed-
back on the KP/NKB/Dyn neurons may be gainfully investigated by the combined
use of KISS1R, TAC3R, and
-opioid receptor agonists and antagonists. KP antag-
onists may also be valuable reagents to determine whether other neurotransmitters
and neuropeptides which stimulate the GnRH neuron do so directly or by stimulat-
ing KP secretion.
μ
Potential Clinical Applications of KP Antagonists
Since KP is a major regulator of GnRH but a degree of GnRH secretion is
KP-independent, KP antagonists might be employed as partial inhibitors of gonado-
tropin and sex steroids. GnRH analogues have found extensive therapeutic applica-
tions in hormone-dependent diseases and in IVF. GnRH agonists induce gonadotrope
desensitisation, while antagonists prevent receptor activation by endogenous GnRH.
Both treatments result in suppression of gonadotropin secretion with consequent
reduction in circulating gonadal steroid hormones. In these treatments, steroid hor-
mones are lowered to castrate levels, resulting in side effects such as hot fl ushes,
reduced lean body mass, loss of libido, and bone loss. Our demonstration that KP
antagonists reduce LH pulsatility and inhibit the ovulatory LH surge, but do not
appear to affect basal LH, suggests that they may fi nd clinical utility in conditions
where maximal suppression of sex steroids is contraindicated. Partial sex steroid
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