The translational use of Kisspeptin and kisspeptin receptor agonists in humans
File(s)
Author(s)
Eng, Pei Chia
Type
Thesis
Abstract
Kisspeptin is a neuropeptide that is known to be a critical regulator of hypothalamic gonadotrophin releasing hormone (GnRH). Physiological studies of kisspeptin have examined the effects of different kisspeptin isoforms (Kisspeptin-10, kisspeptin-54) on GnRH release in men and women. These studies have not only produced new insights into kisspeptin physiology but also paved the way for future studies using kisspeptin as a physiologic, diagnostic and therapeutic tool in individuals with reproductive disorders.
The human kisspeptin peptides, Kisspeptin-10, -13, -14, -54 are named according to their constituent amino acids. Kisspeptin-10, being smaller and easier to synthesize, offers a far more economically viable therapy compared to the longer Kisspeptin-54 peptide. However, due to Kisspeptin-10’s shorter half-life, it requires repeated dosing or prolonged infusion. Kisspeptin receptor agonist (MVT-602) is a modified form of kisspeptin-10 with a longer half-life compared to native kisspeptin-54 (1.5-3.5 hrs vs 0.5 hrs). However, effects of MVT-602 in women have never been determined. By investigating the effects of MVT-602 in healthy women and women with reproductive disorders, I uncovered novel understanding of the effects of MVT-602 in women and demonstrated for the first time that the prolonged and sustained rise of gonadotrophins with MVT-602 can be used as a therapeutic tool in women with reproductive disorders.
Having established the effects of MVT-602 in women, I proceeded to investigate the utility of Kisspeptin-54 to interrogate hypothalamic function in men with Congenital Hypogonadotrophic Hypogonadism (CHH). I have shown that a kisspeptin-54 test, unlike the currently used GnRH test, could offer significant clinical benefit for the accurate diagnosis and management of patients with hypogonadism.
In summary, the data conceived from this thesis have important implications for the development of kisspeptin as a potential therapeutic and diagnostic tool for reproductive pathologies.
The human kisspeptin peptides, Kisspeptin-10, -13, -14, -54 are named according to their constituent amino acids. Kisspeptin-10, being smaller and easier to synthesize, offers a far more economically viable therapy compared to the longer Kisspeptin-54 peptide. However, due to Kisspeptin-10’s shorter half-life, it requires repeated dosing or prolonged infusion. Kisspeptin receptor agonist (MVT-602) is a modified form of kisspeptin-10 with a longer half-life compared to native kisspeptin-54 (1.5-3.5 hrs vs 0.5 hrs). However, effects of MVT-602 in women have never been determined. By investigating the effects of MVT-602 in healthy women and women with reproductive disorders, I uncovered novel understanding of the effects of MVT-602 in women and demonstrated for the first time that the prolonged and sustained rise of gonadotrophins with MVT-602 can be used as a therapeutic tool in women with reproductive disorders.
Having established the effects of MVT-602 in women, I proceeded to investigate the utility of Kisspeptin-54 to interrogate hypothalamic function in men with Congenital Hypogonadotrophic Hypogonadism (CHH). I have shown that a kisspeptin-54 test, unlike the currently used GnRH test, could offer significant clinical benefit for the accurate diagnosis and management of patients with hypogonadism.
In summary, the data conceived from this thesis have important implications for the development of kisspeptin as a potential therapeutic and diagnostic tool for reproductive pathologies.
Version
Open Access
Date Issued
2020-04
Date Awarded
2020-08
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Abbara, Ali
Dhillo, Waljit
Comninos, Alexander
Sponsor
National Institute for Health Research (NIHR)
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)