Kisspeptin antagonists as novel regulators of reproductive function..................
Lead Research Organisation:
MRC Centre for Reproductive Health
Department Name: UNLISTED
Abstract
The reproductive system is controlled by hormones secreted from the hypothalamic region of the brain to control the pituitary gland, which in turn control the ovaries and testes. Recently a new control system within the brain has been discovered, the Kisspeptin system. Kisspeptin is a brain hormone that stimulates the reproductive system and is essential for mediating the onset of puberty. It also plays a part in the normal regulation of reproductive activity in both men and women. In women, Kisspeptin is particularly active in the lead up to ovulation. It is also involved in linking the reproductive system with metabolism and food intake, disorders of which are a common cause of reproductive problems
To really establish the precise role of the Kisspeptin system in normal reproductive function and in disease, it is necessary to develop an antagonist which blocks the activity of the system. We are the first to develop such a drug, and propose to use it to demonstrate the role of Kisspeptin in both men and women. This will be the first time that the full exploration of the Kisspeptin system has been possible and has the potential for new treatments for a wide range of disorders such as endometriosis, fibroids and breast and prostate cancer, as well as in problems of ovulation and in IVF.
To really establish the precise role of the Kisspeptin system in normal reproductive function and in disease, it is necessary to develop an antagonist which blocks the activity of the system. We are the first to develop such a drug, and propose to use it to demonstrate the role of Kisspeptin in both men and women. This will be the first time that the full exploration of the Kisspeptin system has been possible and has the potential for new treatments for a wide range of disorders such as endometriosis, fibroids and breast and prostate cancer, as well as in problems of ovulation and in IVF.
Technical Summary
The Kisspeptins are a family of peptide hormones recently identified as being of central importance in the regulation of the hypothalamic-pituitary-gonadal axis. Specifically these hormones simulate GnRH activity, providing a higher level of control of what has previously been regarded as the main driver of reproductive function. Research in animals has shown that Kisspeptins play a role in the link between metabolic disorders and reproductive function, and in both the negative and positive feedback regulation of GnRH secretion by sex steroids. They also have a major role in the onset of puberty. Their physiological and pathophysiological role in humans is unclear. To further explore this, a Kisspeptin antagonist is required, and we have now developed such a peptide. We propose to administer this antagonist to explore the physiological role of Kisspeptins in the regulation of gonadotropin secretion in normal men initially, which will also allow establish safety and tolerability. Subsequent studies will explore its role in a physiological hypergonadotropic condition i.e. in postmenopausal women. We will then explore its role in a pathophysiological condition characterised by hypersecretion of LH, polycystic ovarian syndrome which also has a major metabolic component. These studies will involve double blind placebo controlled administration of the drug with assessment of pulsatile LH secretion as the primary outcome. We will determine effects of different doses both intravenously and subcutaneously. This class of compounds offers opportunities for novel therapeutics in the treatment of hormone dependant disease including breast and prostate cancer, uterine fibroids and endometriosis, disorders of ovulation, and control of ovarian function during assisted conception. There is also the possibility of application in contraception. The high level of expression of Kisspeptin by the placenta and effects on trophoblast invasion suggest application in disorders of placental function.
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ORCID iD |
RP Millar (Principal Investigator) |
Publications
Evans J
(2008)
Prokineticin 1 signaling and gene regulation in early human pregnancy.
in Endocrinology
Gaytán F
(2009)
KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction.
in American journal of physiology. Endocrinology and metabolism
Pampillo M
(2009)
Regulation of GPR54 signaling by GRK2 and {beta}-arrestin.
in Molecular endocrinology (Baltimore, Md.)
Pineda R
(2010)
Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist.
in Endocrinology
Reynolds RM
(2009)
A role for kisspeptins in pregnancy: facts and speculations.
in Reproduction (Cambridge, England)
Roseweir AK
(2009)
The role of kisspeptin in the control of gonadotrophin secretion.
in Human reproduction update
Roseweir AK
(2009)
Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation.
in The Journal of neuroscience : the official journal of the Society for Neuroscience