Kisspeptin Antagonists - Kisspeptin Signaling in Reproductive Biology - page 180

suppression with KP antagonists may fi nd utility in benign prostatic hyperplasia,
endometriosis, and uterine fi broids, where lowering of gonadal steroids could
improve the conditions without the side effects of reducing steroid hormones to
castrate levels. Polycystic ovarian syndrome (PCOS), which is characterised by
increased LH pulse frequency and increased ratio to FSH, is another potential target
of KP therapy. Although unproven, lowering of GnRH pulse frequency by KP
antagonists should maintain FSH (favoured by low pulse frequency) while lowering
LH, as desired in PCOS. As this would allow follicle development and oestrogen
production, but inhibit ovulation, it may be an attractive possibility as a female con-
traceptive. KP antagonists may also fi nd application in IVF to prevent premature
luteinisation while maintaining basal LH, which may be of value in some women
during superovulation [ 42 , 43 ].
Conclusion
The discovery of KP antagonists provides a new avenue for investigating the role of
KP in the normal physiology of gonadotropin regulation (Fig. 8.14 ) and in patho-
logical conditions. They also offer possibilities in new therapeutic approaches in the
treatment of hormone-dependent diseases without generating side effects of total
ablation of gonadal steroids seen in current therapies.
References
1. Centeno ML et al (2007) Hypothalamic gonadotrophin-releasing hormone expression in
female monkeys with different sensitivity to stress. J Neuroendocrinol 19(8):594-604
2. Porkka-Heiskanen T et al (1997) Rapid photoperiod-induced increase in detectable GnRH
mRNA-containing cells in Siberian hamster. Am J Physiol 273(6 Pt 2):R2032-R2039
3. Millar RP (2005) GnRHs and GnRH receptors. Anim Reprod Sci 88(1-2):5-28
4. Popa SM, Clifton DK, Steiner RA (2008) The role of kisspeptins and GPR54 in the neuroen-
docrine regulation of reproduction. Annu Rev Physiol 70:213-238
5. Roseweir AK, Millar RP (2009) The role of kisspeptin in the control of gonadotrophin secre-
tion. Hum Reprod Update 15(2):203-212
6. Seminara SB et al (2003) The GPR54 gene as a regulator of puberty. N Engl J Med
349(17):1614-1627
7. de Roux N et al (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-
derived peptide receptor GPR54. Proc Natl Acad Sci U S A 100(19):10972-10976
8. Smith JT et al (2005) Differential regulation of KiSS-1 mRNA expression by sex steroids in
the brain of the male mouse. Endocrinology 146(7):2976-2984
9. Smith JT et al (2007) KiSS-1 messenger ribonucleic acid expression in the hypothalamus of
the ewe is regulated by sex steroids and season. Endocrinology 148(3):1150-1157
10. Pompolo S et al (2006) Colocalization of kisspeptin and gonadotropin-releasing hormone in
the ovine brain. Endocrinology 147(2):804-810
11. Shibata M et al (2007) Evidence that down regulation of hypothalamic KiSS-1 expression is
involved in the negative feedback action of testosterone to regulate luteinising hormone secre-
tion in the adult male rhesus monkey (Macaca mulatta). J Neuroendocrinol 19(6):432-438