Kisspeptin in the normal and pathological conditions

DOI

https://dx.doi.org/10.18565/aig.2023.173

Tereschenko I.V.
Professorial Clinic, Perm, Russia

Kisspeptin is a neuropeptide that is produced in the hypothalamus and has a diverse effect on the body. The role of kisspeptin is still under study.
The objective of the presented review is to analyze recent publications on the effect of kisspeptin in the body in normal and pathological conditions.
The literature search was carried out according to the following criteria: the keyword ‘kisspeptin’ was used, publications were chosen mainly for the last 5 years; Russian literature sources were searched mainly in the publications reviewed by the State Commission for Academic Degrees and Titles, foreign sources were in the databases and services, namely PubMed, Google, and Scope.
Kisspeptin has been shown to stimulate the production of gonadotropin-releasing hormone of the hypothalamus and cause its pulsating secretion. In normal conditions, it initiates the onset of puberty, causes the development of egg cells, ovulation in women, high-quality spermatogenesis in men; moreover, it participates in conception, implantation of a fertilized egg, embryo development, placentation, provides energy homeostasis in a pregnant woman, childbirth. During pregnancy, kisspeptin is also produced by the placenta. Kisspeptin secretion is impaired in polycystic ovary syndrome, endometriosis, obesity, pregnancy complications (preeclampsia, gestational diabetes mellitus, risk of miscarriage). The role of kisspeptin in carcinogenesis is studied. Anorexigenic properties of kisspeptin have been revealed. The review includes a description of the synthesized drugs of kisspeptin and its receptor agonists.
Conclusion: In the future, it is possible to use kisspeptin in the treatment of anovulation, infertility, hypogonadism, obesity, pregnancy complications, non-alcoholic fatty liver disease and probably cancer.

Conflicts of interest: Author declares lack of the possible conflicts of interests.
Funding: The study was conducted without sponsorship.
For citation: Tereschenko I.V. Kisspeptin in the normal and pathological conditions.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2024; (2): 37-43 (in Russian)
https://dx.doi.org/10.18565/aig.2023.173

kisspeptin

luliberin

gonadotropins

estrogens

puberty

menopause

hypothalamus

reproduction

fertility

metabolism

Full text (in Russian)

Tsutsui K., Bentley G.E., Kriegsfeld L.J., Osugi T., Seong J.Y., Vaudry H. Discovery and evolutionary history of GnIH and kisspeptin: new key neuropeptides controlling reproduction. J. Neuroendocrinol. 2010; 22(7): 716-27. https://dx.doi.org/10.1111/j.1365-2826.2010.02018.x.
Padda J., Khalid K., Moosa A., Syam M., Kakani V., Imdad U. et al. Role of kisspeptin on hypothalamic-pituitary-gonadal pathology and its effect on reproduction. Cureus. 202; 13(8): e17600. https://dx.doi.org/10.7759/cureus.17600.
Roseweir A.K., Millar R.P. The role of kisspeptin in the control of gonadotrophin secretion. Hum. Reprod. Update. 2009; 15(2): 203-12. https://dx.doi.org/10.1093/humupd/dmn058.
Xie Q., Kang Y., Zhang C., Xie Y., Wang C., Liu C. et al. The role of kisspeptin in the control of the hypothalamic-pituitary-gonadal axis and reproduction. Front. Endocrinol. (Lausanne). 2022; 13: 925206. https://dx.doi.org/10.3389/fendo.2022.925206.
Sobrino V., Avendaño M.S., Perdices-López C., Jimenez-Puyer M., Tena-Sempere M. Kisspeptins and the neuroendocrine control of reproduction: Recent progress and new frontiers in kisspeptin research. Front. Neuroendocrinol. 2022; 65: 100977. https://dx.doi.org/10.1016/j.yfrne.2021.100977.
Hrabovszky E., Ciofi P., Vida B., Horvath M.C., Keller E., Caraty A. et al. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur. J. Neurosci. 2010; 31(11): 1984-98. https://dx.doi.org/10.1111/j.1460-9568.2010.07239.x.
Sharma B., Koysombat K., Comninos A.N., Dhillo W.S., Abbara A. Use of kisspeptin to trigger oocyte maturation during in vitro fertilization (IVF) treatment. Front. Endocrinol. (Lausanne). 2022; 13: 972137. https://dx.doi.org/10.3389/fendo.2022.972137.
Kavanagh G.S., Tadi J., Balkenhol S.M., Kauffman A.S., Maloney S.K., Smith J.T. Kisspeptin impacts on circadian and ultradian rhythms of core body temperature: Evidence in kisspeptin receptor knockout and kisspeptin knockdown mice. Mol. Cell. Endocrinol. 2022; 542: 111530. https://dx.doi.org/10.1016/j.mce.2021.111530.
Никитина И.Л., Байрамов А.А., Ходулева Ю.Н., Шабанов П.Д. Кисспептины в физиологии и патологии полового развития - новые диагностические и терапевтические возможности. Обзоры по клинической фармакологии и лекарственной терапии. 2014; 12(4): 3-13. [Nikitina I.L., Bayramov A.A., Khoduleva Yu.N., Shabanov P.D. Kisspeptins in the physiology and pathology of sexual development - new diagnostic and therapeutic possibilities. Reviews on Clinical Pharmacology and Drug Therapy. 2014; 12(4): 3-13. (in Russian)].
Никитина И.Л., Юхлина Ю.Н., Васильева Е.Ю., Нагорная И.И. Кисспептиновые механизмы регуляции полового развития мальчиков: потенциал диагностики и терапии при задержке старта пубертата и гипогонадотропном гипогонадизме. Проблемы эндокринологии. 2018; 64(5): 280-5. [Nikitina I.L., Yukhlina Yu.N., Vasilyeva E.Yu., Nagornaya I.I. Kisspeptin mechanisms of regulation of sexual development in boys: the potential for diagnosis and therapy in delayed onset of puberty and hypogonadotropic hypogonadism. Problems of Endocrinology. 2018; 64(5): 280-5. (in Russian)]. https://dx.doi.org/10.14341/probl9360.
Bhattacharya M., Babwah A.V. Kisspeptin: beyond the brain. Endocrinology. 2015; 156(4): 1218-27. https://dx.doi.org/10.1210/en.2014-1915.
Nagy Z., Herbison A., Kwakowsky A., Kovacs G., Barabas K. Editorial: Estrogen effects on fertility and neurodegeneration - classical versus non-classic al actions. Front. Endocrinol. (Lausanne). 2023; 14: 1192671. https://dx.doi.org/10.3389/fendo.2023.1192671.
Clarke H., Dhillo W.S., Jayasena C.N. Comprehensive review on kisspeptin and its role in reproductive disorders. Endocrinol. Metab. (Seoul). 2015; 30(2): 124-41. https://dx.doi.org/10.3803/EnM.2015.30.2.124.
Jayasena C.N., Nijher G.M.K., Comninos A.N., Abbara A., Januszewki A., Vaal M.L. et al. The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. J. Clin. Endocrinol. Metab. 2011; 96(12): E19639-72. https://dx.doi.org/10.1210/jc.2011-140.
Moalla M., Kacem F.H., Al-Mutery A.F., Mahfood M., Mejdoub-Rekik N., Abid M. et al. Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism. J. Assist. Reprod. Genet. 2019; 36(6): 1273-80. https://dx.doi.org/10.1007/s10815-019-01468-z.
Abbara A., Eng P.C., Phylactou M., Clarke S.A., Mills E., Chia G. et al. Kisspeptin-54 accurately identifies hypothalamic gonadotropin-releasing hormone neuronal dysfunction in men with congenital hypogonadotropic hypogonadism. Neuroendocrinology. 2021; 111(12): 1176-86. https://dx.doi.org/10.1159/000513248.
Chelaghma N., Rajkanna J., Trotman J., Fuller G., Elsey T., Park S.M., Oyibo S.O. Normosmic idiopathic hypogonadotrophic hypogonadism due to a rare KISS1R gene mutation. Endocrinol. Diabetes Metab. Case Rep. 2018; 2018: 18-0028. https://dx.doi.org/10.1530/EDM-18-0028.
Valdes-Socin H., Almanza M.R., Fernández-Ladreda M.F., Debray F.G., Bours V., Beckers A. Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes. Front. Endocrinol. (Lausanne). 2014; 5: 109. https://dx.doi.org/10.3389/fendo.2014.00109.
Pagani S., Calcaterra V., Acquafredda G., Montalbano C., Bozzola E., Ferrara P. et al. MKRN3 and KISS1R mutations in precocious and early puberty. Ital. J. Pediatr. 2020; 46: 39. https://doi.org/10.1186/s13052-020-0808-6.
Tang R., Ding X., Zhu J. Kisspeptin and polycystic ovary syndrome. Front. Endocrinol. (Lausanne). 2019; 10: 298. https://dx.doi.org/10.3389/fendo.2019.00298.
Wang T., Han S., Tian W., Zhao M., Zhang H. Effects of kisspeptin on pathogenesis and energy metabolism in polycystic ovarian syndrome (PCOS). Gynecol. Endocrinol. 2019; 35(9): 807-10. https://dx.doi.org/10.1080/09513590.2019.1597343.
Pérez-López F.R., Ornat L., López-Baena M.T., Santabárbara J., Savirón-Cornudella R., Pérez-Roncero G.R. Circulating kisspeptin and anti-müllerian hormone levels, and insulin resistance in women with polycystic ovary syndrome: A systematic review, meta-analysis, and meta-regression. Eur. J. Obstet. Gynecol. Reprod. Biol. 2021; 260: 85-98. https://dx.doi.org/10.1016/j.ejogrb.2021.03.007.
Akad M., Socolov R., Covali R., Stan C.D., Crauctuc E., Popovici D. et al. Kisspeptin serum levels in patients with endometriosis, new research pathways regarding female infertility. Maedica (Bucur.). 2022; 17(3): 557-60. https://dx.doi.org/10.26574/maedica.2022.17.3.557.
Asare-Anane H., Ofori E.K., Kwao-Zigah G., Ateko R.O., Annan B.D.R.T., Adjei A.B. et al. Lower circulating kisspeptin and primary hypogonadism in men with type 2 diabetes. Endocrinol. Diabetes Metab. 2019; 2(3): e00070. https://dx.doi.org/10.1002/edm2.70.
Sithinamsuwan K., Mahachoklertwattana P., Wankanit S., Chanprasertyothin S., Pongratanakul S., Khlairit P. et al. Serum kisspeptin and its relation to metabolic parameters and glucose metabolism in prepubertal and pubertal obese children. J. Endocrinol. 2020; 10: 8826401. https://dx.doi.org/10.1155/2020/8826401.
De Bond J.A., Smith J.T. Kisspeptin and energy balance in reproduction. Reproduction. 2014; 147(3): R53-63. https://dx.doi.org/10.1530/REP-13-0509.
Shalitin S., Gat-Yablonski G. Associations of obesity with linear growth and puberty. Horm. Res. Paediatr. 2022; 95(2): 120-36. https://dx.doi.org/10.1159/000516171.
Adams J., Franks S., Polson D.W., Mason H.D., Abdulwahid N., Tucker M. et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet. 1985; 2(8469-70): 1375-9. https://dx.doi.org/10.1016/s0140-6736(85)92552-8.
Воднева Д.Н., Шмаков Р.Г., Щеголев А.И. Роль маркеров инвазии трофобласта в развитии преэклампсии и опухолевой прогрессии. Акушерство и гинекология. 2013; 11: 9-12. [Vodneva D.N., Shmakov R.G., Shchegolev A.I. Role of markers for trophoblast invasion in the development of preeclampsia and tumor progression. Obstetrics and Gynecology. 2013; (11): 9-12. (in Russian)].
Tsoutsouki J., Patel B., Comninos A.N., Dhillo W.S., Abbara A. et al. Kisspeptin in the prediction of pregnancy complications. Front. Endocrinol. (Lausanne). 2022; 13: 942664. https://dx.doi.org/10.3389/fendo.2022.942664.
Matsui H., Asami T. Effects and therapeutic potentials of kisspeptin analogs: regulation of the hypothalamic-pituitary-gonadal axis. Neuroendocrinology. 2014; 99(1): 49-60. https://dx.doi.org/10.1159/000357809.
Hu K.L., Chen Z., Li X., Cai E., Yang H., Chen Y. et al. Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction. Reprod. Biol. Endocrinol. 2022; 20(1): 81. https://dx.doi.org/10.1186/s12958-022-00953-y.
Lippincott M.F., Chan Y.-M., Morales D.R., Seminara S.B. Continuous kisspeptin administration in postmenopausal women: impact of estradiol on luteinizing hormone secretion. J. Clin. Endocrinol. Metab. 2017;102(6): 2091-9. https://dx.doi.org/10.1210/jc.2016-3952.
Navarro V.M. Metabolic regulation of kisspeptin - the link between energy balance and reproduction. Nat. Rev. Endocrinol. 2020; 16(8): 407-20. https://dx.doi.org/10.1038/s41574-020-0363-7.
Hestiantoro A., Astuti B.P.K., Muharam R., Pratama G., Witjaksono F., Wiweko B. Dysregulation of kisspeptin and leptin, as anorexigenic agents, plays role in the development of obesity in postmenopausal women. Int. J. Endocrinol. 2019; 2019: 1347208. https://dx.doi.org/10.1155/2019/1347208.
Abbas S.J., Abed F.S., Dhefer I.H. Does kisspeptin act as a neuropeptide or as an adipokine in obese people? J. Taibah. Univ. Med. Sci. 2022; 17(1): 45-50. https://dx.doi.org/10.1016/j.jtumed.2021.07.010.
Rashad N.M., Al-Sayed R.M., Yousef M.S., Saraya Y.S. Kisspeptin and body weight homeostasis in relation to phenotypic features of polycystic ovary syndrome; metabolic regulation of reproduction. Diabetes Metab. Syndr. 2019; 13(3): 2086-92. https://dx.doi.org/10.1016/j.dsx.2019.04.017.
Izzi-Engbeaya C., Choudhury M.M., Patel B., Muzi B., Qayuum A., Mills E.G. The effects of kisspeptin on food intake in women with overweight or obesity. Diabetes Obes. Metab. 2023; 25(8): 2393-7. https://dx.doi.org/10.1111/dom.15086.
Shamas S., Rani S., Afsheen S., Shahab M., Ejaz R., Sadia H. et al. Changes in irisin release in response to peripheral kisspeptin-10 administration in healthy and obese adult men. Acta Endocrinol. (Buchar.). 2019; 15(3): 283-8. https://dx.doi.org/10.4183/aeb.2019.283.
Wolfe A., Hussain M.A. The emerging role(s) for kisspeptin in metabolism in mammals. Front. Endocrinol. (Lausanne). 12018; 9: 184. https://dx.doi.org/10.3389/fendo.2018.00184.
Huang C., Wang H.Y., Wang M.E., Hsu M.C., Wu Y.S., Jiang Y.F. et al. Kisspeptin-activated autophagy independently suppresses non-glucose-stimulated insulin secretion from pancreatic β-cells. Sci. Rep. 2019; 9(1): 17451. https://dx.doi.org/10.1038/s41598-019-53826-7.
Маевская М.В., Ивашкин В.Т., Ивашкин К.В., Луньков В.Д., Люсина Е.О., Зозюля В.Н., Лещенко В.И. Неалкогольная жировая болезнь печени как причина и следствие кардиометаболических осложнений. Особенности фармакотерапии. Место урсодезоксихолевой кислоты. Терапевтический Архив. 2019;91(2): 109-17. [Maevskaya M.V., Ivashkin V.T., Ivashkin K.V., Lunkov V.D., Lyusina E.O. Non-alcoholic fatty liver disease as a cause and consequence of cardiometabolic complications. Features of pharmacotherapy. Location of ursodeoxycholic acid. Therapeutic Archive. 2019; 91((2): 109-17. (in Russian)]. https://dx.doi.org/10.26442/00403660.2019.02.000122.
Guzman S., Dragan M., Kwon H., de Oliveira V., Rao S., Bhatt V. et al. Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model. J. Clin. Invest. 2022; 132(10): e145889. https://dx.doi.org/10.1172/JCI145889.
Ly T., Harihar S., Welch D.R. KISS1 in metastatic cancer research and treatment: potential and paradoxes. Cancer Metastasis Rev. 2020; 39(3): 739-54. https://dx.doi.org/10.1007/s10555-020-09868-9.
Dragan M., Nguyen M.-U., Guzman S., Goertzen C., Brackstone M., Dhillo W.S. et al. G protein-coupled kisspeptin receptor induces metabolic reprograming and tumorigenesis in estrogen receptor-negative breast cancer. Cell. Death Dis. 2020; 11(2): 106. https://dx.doi.org/10.1038/s41419-020-2305-7.
Gowkielewicz M., Lipka A., Piotrowska A., Szadurska-Noga M., Nowakowski J.J., Lepiarczyk E. et al. Kisspeptin and GPR54 receptor expression in endometrial cancer tissue. Cancers (Basel). 2023; 15(4): 1228. https://dx.doi.org/10.3390/cancers15041228.
Kim T.H., Cho S.G. Kisspeptin inhibits cancer growth and metastasis via activation of EIF2AK2. Mol. Med. Rep. 2017; 16(5): 7585-90. https://dx.doi.org/10.3892/mmr.2017.7578.
Ciaramella V., Corte C.M.D., Ciardiello F., Morgillo F. Kisspeptin and cancer: molecular interaction, biological functions, and future perspectives. Front. Endocrinol. (Lausanne). 2018; 9: 115. https://dx.doi.org/10.3389/fendo.2018.0011.
Ulasov I.V., Borovjagin A.V., Timashev P., Cristofanili M., Welch D.R. KISS1 in breast cancer progression and autophagy. Cancer Metastasis Rev. 2019; 38(3): 493-506. https://dx.doi.org/10.1007/s10555-019-09814-4.
Guzman S., Brackstone M., Radovick S., Babwah A.V., Bhattacharya M.M. KISS1/KISS1R in cancer: friend or foe? Front. Endocrinol. (Lausanne). 2018; 9: 437. https://dx.doi.org/10.3389/fendo.2018.00437.

Received 13.07.2023

Accepted 25.12.2023

Irina V. Tereshchenko, Dr. Med. Sci., Professor, endocrinologist, MC «Professorial clinic», 614000, Russia, Perm, Druzhby str., 15А, i_v_t@bk.ru,
https://orcid.org/0000-0002-0390-3649

Kisspeptin in the normal and pathological conditions

Tereschenko I.V.

Keywords

References

About the Authors

Similar Articles