Effect of kisspeptin, neurokinin, and dynorphin neurons on regulation of reproduction

Česká verze

Authors: Jana Racková ^1,2
Authors place of work: Gynovum s. r. o., Mochov ¹; Gynem s. r. o., Praha ²
Published in the journal: Ceska Gynekol 2025; 90(5): 413-417
Category: Přehledová práce
doi: https://doi.org/10.48095/cccg2025413

Summary

Gonadotropin-releasing hormone pulsatility is under the influence of hypothalamic neuropeptides, especially neurons expressing kisspeptin, neurokinin B, and dynorphin. These hypothalamic cells are called KNDy neurons. By integrating hormonal and environmental stimuli in the brain, they modulate the effects on neuropeptide release and control the frequency and amplitude of pulses. The relationship between KNDy neurons and gonadal hormones is essential for the initiation of puberty, regulation of the menstrual cycle, and reproduction. Steroid hormones have a feedback effect on the modulation of the activity of KNDy neurons, as their membrane and cell nucleus express receptors for estradiol, progesterone, and testosterone. Recent research suggests a close relationship with the pathophysiology of infertility, pathological pregnancy, menstrual cycle disorders, polycystic ovary syndrome, endometriosis, and vasomotor symptoms in perimenopause.

Keywords:

Endometriosis – reproduction – Polycystic ovary syndrome – menstrual cycle – menopause – kisspeptin – neurokinin – dynorphin

Zdroje

1. Kochman K. Evolution of gonadotropin-releasing hormone (GnRH) structure and its receptor. J Anim Feed Sci 2012; 21 (1): 3–30. doi: 10.22358/jafs/66031/2012.

2. Herbison AE, Theodosis DT. Localization of oestrogen receptors in preoptic neurons containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone-releasing hormone in the male and female rat. Neuroscience 1992; 50 (2): 283–298. doi: 10.1016/0306-4522 (92) 90423-y.

3. Uenoyama Y, Inoue N, Nakamura S et al. Kisspeptin neurons and Estrogen-Estrogen Receptor a signaling: unraveling the mystery of steroid feedback system regulating mammalian reproduction. Int J Mol Sci 2021; 22 (17): 9229. doi: 10.3390/ijms22179229.

4. Skinner DC, Evans NP, Delaleu B et al. The negative feedback actions of progesterone on gonadotropin-releasing hormone secretion are transduced by the classical progesterone receptor. Proc Natl Acad Sci U S A 1998; 95 (18): 10978–10983. doi: 10.1073/pnas.95.18. 10978.

5. Xie Q, Kang Y, Zhang C et al. The role of Kisspeptin in the control of the hypothalamic-pituitary-gonadal axis and reproduction. Front Endocrinol (Lausanne) 2022; 13 : 925206. doi: 10.3389/fendo.2022.925206.

6. Navarro VM. Metabolic regulation of kisspeptin –⁠ the link between energy balance and reproduction. Nat Rev Endocrinol 2020; 16 (8): 407–420. doi: 10.1038/s41574-020-0363-7.

7. Hussain MA, Song WJ, Wolfe A. There is Kisspeptin –⁠ and then there is Kisspeptin. Trends Endocrinol Metab 2015; 26 (10): 564–572. doi: 10.1016/j.tem.2015.07.008.

8. Mills EG, Dhillo WS, Comninos AN. Kisspeptin and the control of emotions, mood and reproductive behaviour. J Endocrinol 2018; 239 (1): R1–R12. doi: 10.1530/JOE-18-0269.

9. Gorbunova OL, Shirshev SV. Role of Kisspeptin in regulation of reproductive and immune reactions. Biochemistry (Mosc) 2020; 85 (8): 839–853. doi: 10.1134/S0006297920080015.

10. Ruohonen ST, Poutanen M, Tena-Sempere M. Role of kisspeptins in the control of the hypothalamic-pituitary-ovarian axis: old dogmas and new challenges. Fertil Steril 2020; 114 (3): 465–474. doi: 10.1016/j.fertnstert.2020. 06.038.

11. Clarkson J, Han SY, Piet R et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc Natl Acad Sci U S A 2017; 114 (47): E10216–E10223. doi: 10.1073/pnas.1713897114.

12. Atre I, Mizrahi N, Levavi-Sivan B. Characteristics of Neurokinin-3 receptor and its binding sites by mutational analysis. Biology (Basel) 2021; 10 (10): 968. doi: 10.3390/biology 10100968.

13. Abbara A, Eng PC, Phylactou M et al. Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders. J Clin Invest 2020; 130 (12): 6739–6753. doi: 10.1172/JCI139681.

14. Hu KL, Chang HM, Zhao HC et al. Potential Roles for the kisspeptin/kisspeptin receptor system in implantation and placentation. Hum Reprod Update 2019; 25 (3): 326–343. doi: 10.1093/humupd/dmy046.

15. Park DW, Lee SK, Hong SR et al. Expression of Kisspeptin and its receptor GPR54 in the first trimester trophoblast of women with recurrent pregnancy loss. Am J Reprod Immunol 2012; 67 (2): 132–139. doi: 10.1111/j.1600-0897. 2011.01073.x.

16. Racková J, Driák D, Neumannová H et al. Use of methotrexate in the ectopic pregnancy and pregnancy of unknown location. Ceska Gynekol 2016; 81 (2): 140–146.

17. Tsoutsouki J, Patel B, Comninos AN et al. Kisspeptin in the prediction of pregnancy complications. Front Endocrinol (Lausanne) 2022; 13 : 942664. doi: 10.3389/fendo.2022.942664.

18. Dinsdale N, Nepomnaschy P, Crespi B. The evolutionary biology of endometriosis. Evol Med Public Health 2021; 9 (1): 174–191. doi: 10.1093/emph/eoab008.

19. Gorbunova O, Shirshev S. The effect of kisspeptin on the functional activity of peripheral blood monocytes and neutrophils in the context of physiological pregnancy. J Reprod Immunol 2022; 151 : 103621. doi: 10.1016/j.jri.2022.103621.

20. Liu H, Wang J, Wang H et al. Correlation between matrix metalloproteinase-9 and endometriosis. Int J Clin Exp Pathol 2015; 8 (10): 13399–13404.

21. Akad M, Socolov R, Furnică C et al. Kisspeptin variations in patients with polycystic ovary syndrome –⁠ a prospective case control study. Medicina (Kaunas) 2022; 58 (6): 776. doi: 10.3390/medicina58060776.

22. Fraser GL, Obermayer-Pietsch B, Laven J et al. Randomized controlled trial of Neurokinin 3 receptor antagonist fezolinetant for treatment of polycystic ovary syndrome. J Clin Endocrinol Metab 2021; 106 (9): e3519–e3532. doi: 10.1210/clinem/dgab320.

23. Rance NE. Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 2009; 30 (1) : 111 –⁠ 122. doi: 10.1016/ j.peptides.2008.05.016.

ORCID autorky

J. Racková 0000-0001-7647-4905

Doručeno/ Submitted: 3. 6. 2025

Přijato/ Accepted: 26. 6. 2025

MU Dr. Jana Racková

Gynovum s. r. o.

Na Dolejšku 286

250 87 Mochov

gynovum.rackova@gmail.com