Evaluating the potential utility of kisspeptin to treat reproductive disorders

Abstract

The kisspeptins, encoded by the KISS1 gene, are a group of newly discovered peptides, which have been found to play an important regulatory role in human reproduction. Loss of function mutations of kisspeptin or the kisspeptin receptor have been shown to cause pubertal failure; whereas activating mutations cause precocious puberty. Central and peripheral administration of kisspeptin to mammals stimulates gonadotrophin secretion via gonadotrophin releasing hormone (GnRH) stimulation. Similar observations have been reported in human studies as well as an increase in luteinizing hormone (LH) pulsatility. Kisspeptin is now known to be associated with brain sexual differentiation, sexual dimorphism, pubertal initiation and sex steroids feedback loops, which will be discussed in this review. Metabolic state, stress, and other neuropeptides such as neurokinin B (NKB) are associated with changes in kisspeptin's stimulatory action. The conclusions from kisspeptin studies so far have led to the consideration of potential therapeutic applications, which will be discussed. Increasing our understanding of kisspeptin may aid our knowledge and management of infertility, contraception and hormone sensitive conditions.

Keywords::

• dynorphin
• follicle-stimulating hormone
• gonadotrophin-releasing hormone
• hypogonadotrophic hypogonadism
• infertility
• kisspeptin
• KNDy
• leptin
• luteinizing hormone
• neurokinin B

Financial & competing interests disclosure

JT Mogford was supported by a NIHR Academic Clinical Fellowship. WS Dhillo was supported by a NIHR Career Development Fellowship. CN Jayasena was supported by a NIHR Clinical Lectureship, Society for Endocrinology Early Career Grant and Academy of Medical Sciences/Wellcome Starter Grant for Clinical Lectures. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism, whereas activating GPR54 mutations cause precocious puberty.

• Kisspeptin causes the pituitary gland to secrete luteinizing hormone and follicle-stimulating hormone through a gonadotrophin-releasing hormone-dependent pathway in all animal species tested and man; tachyphylaxis can be seen with chronic use.

• Kisspeptin is involved in brain sexual differentiation, pubertal initiation and the generation of the preovulatory surge of luteinizing hormone in mammals.

• Kisspeptin use may become therapeutic for fertility treatment, contraception and the management of hormone-sensitive conditions.