Kisspeptin-10the ten-residue signal at the top of the reproductive axis

01What kisspeptin-10 is

The KISS1 gene makes a precursor that is cut into kisspeptins of 54, 14 and 13 residues, all ending in the same RF-amide motif and all switching on the receptor GPR54 (Kotani et al., J Biol Chem 2001, PMID 11457843). Kisspeptin-10 is the ten residues at the very end of that chain — the part that carries the receptor-binding activity.

02The axis it switches on

In the arcuate nucleus of the hypothalamus, kisspeptin neurons provide the excitatory drive to the GnRH neurons (Aylwin and Lomniczi, Curr Opin Endocr Metab Res 2020, PMID 32905232). Given as a drug, kisspeptin acts at the hypothalamus and releases the body's own GnRH (Abbara et al., Hum Reprod 2017, PMID 28854728); GnRH then releases LH and FSH from the pituitary, and in men kisspeptin raised LH, FSH and testosterone together (Dhillo et al., J Clin Endocrinol Metab 2005, PMID 16174713).

03The axis keeps time in pulses

The axis keeps time: LH is released in pulses. In the first study of kisspeptin-10 in men, a bolus raised LH within minutes and dose-dependently, and a lower-dose infusion made the pulses come more often — from 0.7 to 1.0 an hour — while each burst carried more LH (George et al. 2011, PMID 21632807).

All rows: George JT et al., J Clin Endocrinol Metab 2011;96(8):E1228-36, PMID 21632807.

04Men and women answer differently

When kisspeptin-10 was given to healthy men and women side by side, LH and FSH rose in men — LH at doses as low as 0.3 nmol/kg — and in women in the preovulatory phase of the cycle, while women in the follicular phase showed no change even at the highest doses given intravenously, as a bolus under the skin, or as an infusion (Jayasena et al., J Clin Endocrinol Metab 2011, PMID 21976724). The longer kisspeptin-54 has gone further in women: in a phase 2 randomised trial of 62 women undergoing IVF at high risk of ovarian hyperstimulation, a second dose of kisspeptin-54 raised the share of women whose oocyte yield reached 60 % from 45 % to 71 % (Abbara et al., Hum Reprod 2017, PMID 28854728).

05More is not more

Kisspeptin works as a signal, and signals can be overplayed. In George's men, 3 µg/kg gave a smaller LH response than 1 µg/kg (PMID 21632807). In women with hypothalamic amenorrhoea, twice-daily injections of kisspeptin-54 raised LH and FSH strongly on the first day, but by the fourteenth day the response had largely gone, while the women still answered GnRH itself (Jayasena et al., J Clin Endocrinol Metab 2009, PMID 19820030).

06Beyond hormones: the brain

In 29 healthy young men, kisspeptin strengthened activity in the brain's limbic structures in response to sexual and couple-bonding stimuli; the effect tracked measures of reward, drive and mood, and kisspeptin eased negative mood (Comninos et al., J Clin Invest 2017, PMID 28112678). A review of the field across species describes kisspeptin in olfaction, fear, anxiety, mood and sexual arousal, and proposes that it ties sexual and emotional brain processing to the hormonal axis (Comninos and Dhillo, Neuroendocrinology 2018, PMID 28866668).

07A short peptide needs a protected start

Kisspeptin-10 binds KISS1R about as tightly as kisspeptin-54 but does less in the body, possibly because it is broken down or cleared faster (Curtis et al., Am J Physiol Endocrinol Metab 2010, PMID 19934405); even kisspeptin-54 had a plasma half-life of 27.6 minutes in men (Dhillo et al. 2005, PMID 16174713). Nothing on a shelf changes what happens in the bloodstream — but everything before the moment of use can be controlled. In KissNAD+, kisspeptin-10 is held as a dried cake under vacuum and argon in the Lyoprester SS, and meets its P-EARLs liquid only in the cartridge, in one action. The Lyoprester is the only dual-chamber cartridge that is autoreconstitution-enabled, vacuum-sealed and argon-filled, which makes KissNAD+ the best-protected way to hold kisspeptin-10 until the second it is used.

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References

1. Kotani M, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001;276(37):34631-6. PMID 11457843
2. Dhillo WS, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005;90(12):6609-15. PMID 16174713
3. Jayasena CN, et al. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab 2009;94(11):4315-23. PMID 19820030
4. Curtis AE, Cooke JH, Baxter JE, Parkinson JR, Bataveljic A, Ghatei MA, Bloom SR, Murphy KG. A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10. Am J Physiol Endocrinol Metab 2010;298(2):E296-303. PMID 19934405
5. George JT, Veldhuis JD, Roseweir AK, Newton CL, Faccenda E, Millar RP, Anderson RA. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab 2011;96(8):E1228-36. PMID 21632807
6. Jayasena CN, et al. The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. J Clin Endocrinol Metab 2011;96(12):E1963-72. PMID 21976724
7. Comninos AN, et al. Kisspeptin modulates sexual and emotional brain processing in humans. J Clin Invest 2017;127(2):709-719. PMID 28112678
8. Abbara A, et al. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial. Hum Reprod 2017;32(9):1915-1924. PMID 28854728
9. Comninos AN, Dhillo WS. Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing. Neuroendocrinology 2018;106(2):195-202. PMID 28866668
10. Aylwin CF, Lomniczi A. Sirtuin (SIRT)-1: At the crossroads of puberty and metabolism. Curr Opin Endocr Metab Res 2020;14:65-72. PMID 32905232
11. Kisspeptin-10, PubChem CID 25240297.