Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction

Abstract

Background Kisspeptin is the leading upstream regulator of pulsatile and surge Gonadotrophin-Releasing Hormone secretion (GnRH) in the hypothalamus, which acts as the key governor of the hypothalamic-pituitary-ovary axis. Main text Exogenous kisspeptin or its receptor agonist can stimulate GnRH release and subsequent physiological gonadotropin secretion in humans. Based on the role of kisspeptin in the hypothalamus, a broad application of kisspeptin and its receptor agonist has been recently uncovered in humans, including central control of ovulation, oocyte maturation (particularly in women at a high risk of ovarian hyperstimulation syndrome), test for GnRH neuronal function, and gatekeepers of puberty onset. In addition, the kisspeptin analogs, such as TAK-448, showed promising agonistic activity in healthy women as well as in women with hypothalamic amenorrhoea or polycystic ovary syndrome. Conclusion More clinical trials should focus on the therapeutic effect of kisspeptin, its receptor agonist and antagonist in women with reproductive disorders, such as hypothalamic amenorrhoea, polycystic ovary syndrome, and endometriosis.

Urinary gonadotropin assay on 24-h collections as a tool to detect early central puberty onset in girls: determination of predictive thresholds

“…Urinary gonadotropins could be able to supplement for the lack of sensitivity of the GnRH test. The response of the axis to GnRH pulses depends on sex hormone effects, involving activation of kisspeptin neurons ( Cortés et al , 2015 ; Hu et al , 2022 ). In some situations, such as obesity, a highly emerging issue in paediatrics, a non-dynamic assessment of the rise of gonadotropin appears more appropriate than a GnRH test given the effect of leptin on kisspeptin neurons ( Itriyeva, 2022 ).…”

Functional evaluation of a novel kisspeptin analogue on the reproduction of female goldfish

“…Numerous kisspeptin analogs have been synthesized to improve their biological activity and/or stability, including those containing substitutions with unnatural amino acids and/or chemical modifications 13 , 20 . Substitution of Gly-Leu dipeptide bond, which is located at the C-terminal moiety of Kiss1 and is susceptible to proteolytic degradation with metalloproteases, improved its stability against proteolytic degradation 21 .…”

“…Given that milt amount is not considered a limiting factor in the artificial reproduction and most hormonal manipulations are utilized to increase the spawning of female fish, we designed, synthesized, and characterized a new kp-10 analog (M-kp10) to increase reproductive efficiency in female fish. Numerous kisspeptin analogs have been synthesized to improve their biological activity and/or stability, including those containing substitutions with unnatural amino acids and/or chemical modifications 13,20 . Substitution of Gly-Leu dipeptide bond, which is located at the C-terminal moiety of Kiss1 and is susceptible to proteolytic degradation with metalloproteases, improved its stability against proteolytic degradation 21 .…”

“…Numerous kisspeptin analogs have been synthesized in structure–activity studies 13 Based on D-amino acid scanning analysis of human kp-10, the five C-terminal residues, including 6 Phe-Gly-Leu-Arg-Tyr 12 (corresponding to 6 Phe-Gly-Leu-Arg-Phe 10 in teleosts) are stereochemically of high importance for proper kisspeptin receptor activation. Among these residues substitution of either Phe6, Arg9, or Phe10 showed the highest impact on the agonistic activity 14 – 16 .…”

Pharmacotherapy of male hypogonadism

“…selective estrogen modulators (SERMS) and aromatase inhibitors (ARI). Finally, treatments aimed at restoring GnRH pulsatility because of a direct stimulation (kisspeptin analogues) or because of treating hypothalamic metaflammation (Interleukin 1 antagonist) are under evaluation [30,31].…”