Volume 67, December 2022, 102319Author links open overlay panelAbstract

Kisspeptin is a hypothalamic neuropeptide that acts via the hypothalamus to stimulate hypothalamic gonadotrophin-releasing hormone secretion and downstream gonadotrophin release. In health, kisspeptin induces normal puberty and modulates ovulation in healthy women. Hypothalamic kisspeptin expression is reduced in several functional reproductive disorders; thus, treating such conditions with kisspeptin is conceptually attractive. Recent studies have demonstrated that kisspeptin can induce a more physiological degree of oocyte maturation during in vitro fertilisation treatment that can reduce the risk of potentially life-threatening complications such as ovarian hyperstimulation syndrome seen with human chorionic gonadotrophin. Furthermore, chronic use of kisspeptin could potentially restore reproductive health in females with hypothalamic amenorrhoea, treat hyposexual drive disorder in otherwise healthy males and has potential indications in polycystic ovary syndrome, osteoporosis and metabolic dysfunction-associated fatty liver disease. Finally, kisspeptin analogues could potentially overcome some of the pharmacological challenges associated with the natural forms of kisspeptin such as short duration of action and development of tachyphylaxis.

Section snippetsBackground

The kisspeptins are a family of peptides encoded by the KISS1 gene in humans (KISS1 in non-human primates and Kiss1 in other mammals) [1]. The prepropeptide consists of 145 amino acids that is subsequently proteolysed into shorter peptides of lengths denoted by their suffix, such as kisspeptin-54 (KP-54), −14, −13 and −10 (KP-10) [2]. All forms share a common C-terminal decapeptide sequence, equivalent to KP-10, which is important for their binding to the G-protein-coupled kisspeptin receptor,

Kisspeptin trials in healthy men and women

KP-10, KP-54 and kisspeptin receptor agonists such as TAK-683 [11] and MVT-602 (formerly known as TAK-448) [12] are the kisspeptin peptides that have been studied in humans to date. KP-10 is potent against KISS1R in vitro but is not believed to cross the blood–brain barrier and has a shorter half-life than KP-54 (t1/2 3 vs. 28 min) due to significant enzymatic degradation, making it less suitable for bolus administration [2]. Native KP-54 has a longer half-life and induces greater LH rises in

Kisspeptin and oocyte maturation in in vitro fertilisation treatment

According to the World Health Organisation, infertility affects 15% of reproductive-aged couples worldwide, which has led to a rise in the number of couples undergoing in vitro fertilisation (IVF) treatment [38]. In order to prepare the oocytes for surgical retrieval during IVF, LH-like exposure is needed to ‘mature’ them in order that they attain competence for fertilisation by sperm [39]. Approximately, three quarters of IVF cycles use human chorionic gonadotrophin (hCG) to trigger oocyte

Kisspeptin and metabolic dysfunction-associated fatty liver disease

MAFLD is the commonest liver disease, affecting 25% of the population [61]. It is associated with obesity, hyperlipidaemia and type 2 diabetes and can progress to non-alcoholic steatohepatitis, fibrosis, and even cirrhosis [61]. MAFLD is characterised by dysregulated hepatic fat metabolism and accumulation (steatosis).

Kiss1r-knockout mice on high-fat diet developed liver steatosis, glucose intolerance and insulin resistance compared with high-fat diet-fed controls [9]. MVT-602 administration to

Conclusion

Kisspeptin acts via the hypothalamus to stimulate endogenous GnRH secretion and downstream gonadotrophin release. Hypothalamic kisspeptin expression is reduced in several functional reproductive disorders, for example, hyperprolactinaemia [58], obesity [71] and undernutrition-related hypogonadism [57]. Thus, treating such conditions with kisspeptin to replace the deficient kisspeptin is conceptually attractive.

Furthermore, kisspeptin is part of the physiological mechanism of ovulation [72] and

Author contributions

JT wrote the manuscript and designed the figures. AA and WSD reviewed and edited the manuscript and are the corresponding authors. All authors have made a substantial, direct and intellectual contribution to the work and approved the manuscript before its submission.

Funding

This work was supported by grants from the National Institute of Health Research (NIHR), the NIHR/Wellcome Trust Imperial Clinical Research Facility and the NIHR Imperial Biomedical Research Centre. The Section of Endocrinology and Investigative Medicine was funded by grants from the Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC), NIHR and was supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the

Declaration of competing interest

AA and WSD have consulted for Myovant Sciences who are developing a kisspeptin receptor agonist.

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