Kisspeptins Regulating Fertility: Potential Future Therapeutic Approach in Infertility Treatment
Abstract
:1. Introduction
2. Kisspeptins System
3. KNDy Neurons
4. Association of Kisspeptins to Infertility
4.1. Idiopathic Hypogonadotropic Hypogonadism (iHH)
4.2. Hyperprolactinemia
4.3. Primary Ovarian Insufficiency (POI)
4.4. Polycystic Ovary Syndrome (PCOS)
4.5. Endometriosis
4.6. Unexplained Infertility
4.7. Functional Hypothalamic Amenorrhea (FHA)
4.8. Male Factor Infertility
5. Therapeutic Use of Kisspeptins
5.1. Triggering Ovulation
5.2. Ovarian Hyperstimulation Syndrome (OHSS)
5.3. In Vitro Maturation (IVM)
5.4. Cryopreservation
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Zegers-Hochschild, F.; Nygren, K.-G.; Adamson, G.D.; De Mouzon, J.; Lancaster, P.; Mansour, R.; Sullivan, E. The International Committee Monitoring Assisted Reproductive Technologies (ICMART) glossary on ART terminology. Fertil. Steril. 2006, 86, 16–19. [Google Scholar] [CrossRef] [PubMed]
- Njagi, P.; Groot, W.; Arsenijevic, J.; Dyer, S.; Mburu, G.; Kiarie, J. Financial costs of assisted reproductive technology for patients in low- and middle-income countries: A systematic review. Hum. Reprod. Open 2023, 2023, hoad007. [Google Scholar] [CrossRef] [PubMed]
- Seminara, S.B.; Messager, S.; Chatzidaki, E.E.; Thresher, R.R.; Acierno, J.S.; Shagoury, J.K.; Bo-Abbas, Y.; Kuohung, W.; Schwinof, K.M.; Hendrick, A.G.; et al. The GPR54 Gene as a Regulator of Puberty. N. Engl. J. Med. 2003, 349, 1614–1627. [Google Scholar] [CrossRef]
- Panidis, D.; Rousso, D.; Koliakos, G.; Kourtis, A.; Katsikis, I.; Farmakiotis, D.; Votsi, E.; Diamanti-Kandarakis, E. Plasma metastin levels are negatively correlated with insulin resistance and free androgens in women with polycystic ovary syndrome. Fertil. Steril. 2006, 85, 1778–1783. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Brown, R.S.E.; Herbison, A.E.; Grattan, D.R. Lactational Anovulation in Mice Results From a Selective Loss of Kisspeptin Input to GnRH Neurons. Endocrinology 2014, 155, 193–203. [Google Scholar] [CrossRef]
- Irwig, M.S.; Fraley, G.S.; Smith, J.T.; Acohido, B.V.; Popa, S.M.; Cunningham, M.J.; Gottsch, M.L.; Clifton, D.K.; Steiner, R.A. Kisspeptin Activation of Gonadotropin Releasing Hormone Neurons and Regulation of KiSS-1 mRNA in the Male Rat. Neuroendocrinology 2004, 80, 264–272. [Google Scholar] [CrossRef]
- Lee, E.B.; Dilower, I.; Marsh, C.A.; Wolfe, M.W.; Masumi, S.; Upadhyaya, S.; Rumi, M.A.K. Sexual Dimorphism in Kisspeptin Signaling. Cells 2022, 11, 1146. [Google Scholar] [CrossRef]
- Sonigo, C.; Bouilly, J.; Carré, N.; Tolle, V.; Caraty, A.; Tello, J.; Simony-Conesa, F.-J.; Millar, R.; Young, J.; Binart, N. Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration. J. Clin. Investig. 2012, 122, 3791–3795. [Google Scholar] [CrossRef]
- Calik-Ksepka, A.; Stradczuk, M.; Czarnecka, K.; Grymowicz, M.; Smolarczyk, R. Lactational Amenorrhea: Neuroendocrine Pathways Controlling Fertility and Bone Turnover. Int. J. Mol. Sci. 2022, 23, 1633. [Google Scholar] [CrossRef]
- Jayasena, C.N.; Nijher, G.M.K.; Abbara, A.; Murphy, K.G.; Lim, A.; Patel, D.; Mehta, A.; Todd, C.; Donaldson, M.; Trew, G.H.; et al. Twice-Weekly Administration of Kisspeptin-54 for 8 Weeks Stimulates Release of Reproductive Hormones in Women With Hypothalamic Amenorrhea. Clin. Pharmacol. Ther. 2010, 88, 840–847. [Google Scholar] [CrossRef]
- Tavakoli, A.; Azar, A.T.; Taghizabet, N.; Rezaei-Tazangi, F.; Ardebili, S.N.; Mofarahe, Z.S.; Aliakbari, F.; Mehranjani, M.S. The effect of kisspeptin on the maturation of human ovarian follicles in culture following vitrification-thawing processes. JBRA Assist. Reprod. 2023, 27, 668–676. [Google Scholar] [CrossRef] [PubMed]
- Tavakoli, A.; Aliakbari, F.; Mehranjani, M.S. Kisspeptin decreases the adverse effects of human ovarian vitrification by regulating ROS-related apoptotic occurrences. Zygote 2023, 31, 537–543. [Google Scholar] [CrossRef] [PubMed]
- Abbara, A.; Eng, P.C.; Phylactou, M.; Clarke, S.A.; Richardson, R.; Sykes, C.M.; Phumsatitpong, C.; Mills, E.; Modi, M.; Izzi-Engbeaya, C.; et al. Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders. J. Clin. Investig. 2020, 130, 6739–6753. [Google Scholar] [CrossRef] [PubMed]
- Patel, B.; Koysombat, K.; Mills, E.G.; Tsoutsouki, J.; Comninos, A.N.; Abbara, A.; Dhillo, W.S. The Emerging Therapeutic Potential of Kisspeptin and Neurokinin B. Endocr. Rev. 2023, 45, 30–68. [Google Scholar] [CrossRef]
- Roseweir, A.K.; Millar, R.P. The role of kisspeptin in the control of gonadotrophin secretion. Hum. Reprod. Update 2009, 15, 203–212. [Google Scholar] [CrossRef]
- Tng, E.L. Kisspeptin signalling and its roles in humans. Singapore Med. J. 2015, 56, 649–656. [Google Scholar] [CrossRef]
- Lee, J.H.; Welch, D.R. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res. 1997, 57, 2384–2387. [Google Scholar]
- Masui, T.; Doi, R.; Mori, T.; Toyoda, E.; Koizumi, M.; Kami, K.; Ito, D.; Peiper, S.C.; Broach, J.R.; Oishi, S.; et al. Metastin and its variant forms suppress migration of pancreatic cancer cells. Biochem. Biophys. Res. Commun. 2004, 315, 85–92. [Google Scholar] [CrossRef]
- Ohtaki, T.; Shintani, Y.; Honda, S.; Matsumoto, H.; Hori, A.; Kanehashi, K.; Terao, Y.; Kumano, S.; Takatsu, Y.; Masuda, Y.; et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 2001, 411, 613–617. [Google Scholar] [CrossRef]
- de Roux, N.; Genin, E.; Carel, J.-C.; Matsuda, F.; Chaussain, J.-L.; Milgrom, E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl. Acad. Sci. USA 2003, 100, 10972–10976. [Google Scholar] [CrossRef]
- Ruiz-Cruz, M.; Torres-Granados, C.; Tena-Sempere, M.; Roa, J. Central and peripheral mechanisms involved in the control of GnRH neuronal function by metabolic factors. Curr. Opin. Pharmacol. 2023, 71, 102382. [Google Scholar] [CrossRef] [PubMed]
- Pinilla, L.; Aguilar, E.; Dieguez, C.; Millar, R.P.; Tena-Sempere, M. Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms. Physiol. Rev. 2012, 92, 1235–1316. [Google Scholar] [CrossRef] [PubMed]
- Prashar, V.; Arora, T.; Singh, R.; Sharma, A.; Parkash, J. Hypothalamic Kisspeptin Neurons: Integral Elements of the GnRH System. Reprod. Sci. 2023, 30, 802–822. [Google Scholar] [CrossRef]
- Lin, X.-H.; Lass, G.; Kong, L.-S.; Wang, H.; Li, X.-F.; Huang, H.-F.; O’Byrne, K.T. Optogenetic Activation of Arcuate Kisspeptin Neurons Generates a Luteinizing Hormone Surge-Like Secretion in an Estradiol-Dependent Manner. Front. Endocrinol. 2021, 12, 775233. [Google Scholar] [CrossRef]
- Yeo, S.-H.; Colledge, W.H. The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic–Pituitary–Gonadal Axis. Front. Endocrinol. 2018, 9, 188. [Google Scholar] [CrossRef]
- Roa, J.; Castellano, J.M.; Navarro, V.M.; Handelsman, D.J.; Pinilla, L.; Tena-Sempere, M. Kisspeptins and the control of gonadotropin secretion in male and female rodents. Peptides 2009, 30, 57–66. [Google Scholar] [CrossRef]
- Lehman, M.N.; Coolen, L.M.; Goodman, R.L. Minireview: Kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: A central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 2010, 151, 3479–3489. [Google Scholar] [CrossRef]
- Topaloglu, A.K.; Reimann, F.; Guclu, M.; Yalin, A.S.; Kotan, L.D.; Porter, K.M.; Serin, A.; Mungan, N.O.; Cook, J.R.; Imamoglu, S.; et al. TAC3 and TACR3 Mutations in Familial Hypogonadotropic Hypogonadism Reveal a Key Role for Neurokinin B in the Central Control of Reproduction. Nat. Genet. 2009, 41, 354–358. [Google Scholar] [CrossRef]
- Merhi, Z.; Bazzi, A.A.; Bonney, E.A.; Buyuk, E. Role of adiponectin in ovarian follicular development and ovarian reserve. Biomed. Rep. 2019, 10, 337–342. [Google Scholar] [CrossRef]
- Zegers-Hochschild, F.; Adamson, G.D.; Dyer, S.; Racowsky, C.; de Mouzon, J.; Sokol, R.; Rienzi, L.; Sunde, A.; Schmidt, L.; Cooke, I.D.; et al. The International Glossary on Infertility and Fertility Care, 2017. Hum. Reprod. 2017, 32, 1786–1801. [Google Scholar] [CrossRef]
- Chan, Y.M.; Broder-Fingert, S.; Wong, K.M.; Seminara, S.B. Kisspeptin/Gpr54-independent gonadotrophin-releasing hormone activity in Kiss1 and Gpr54 mutant mice. J. Neuroendocrinol. 2009, 21, 1015–1023. [Google Scholar] [CrossRef] [PubMed]
- d’Anglemont de Tassigny, X.; Fagg, L.A.; Dixon, J.P.C.; Day, K.; Leitch, H.G.; Hendrick, A.G.; Zahn, D.; Franceschini, I.; Caraty, A.; Carlton, M.B.L.; et al. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc. Natl. Acad. Sci. USA 2007, 104, 10714–10719. [Google Scholar] [CrossRef] [PubMed]
- Hu, K.-L.; Zhao, H.; Chang, H.-M.; Yu, Y.; Qiao, J. Kisspeptin/Kisspeptin Receptor System in the Ovary. Front. Endocrinol. 2018, 8, 365. [Google Scholar] [CrossRef] [PubMed]
- Jayasena, C.N.; Dhillo, W.S. Kisspeptin offers a novel therapeutic target in reproduction. Curr. Opin. Investig. Drugs Lond. Engl. 2000 2009, 10, 311–318. [Google Scholar]
- Pineda, R.; Garcia-Galiano, D.; Roseweir, A.; Romero, M.; Sanchez-Garrido, M.A.; Ruiz-Pino, F.; Morgan, K.; Pinilla, L.; Millar, R.P.; Tena-Sempere, M. Critical Roles of Kisspeptins in Female Puberty and Preovulatory Gonadotropin Surges as Revealed by a Novel Antagonist. Endocrinology 2010, 151, 722–730. [Google Scholar] [CrossRef]
- Guerriero, K.A.; Keen, K.L.; Millar, R.P.; Terasawa, E. Developmental Changes in GnRH Release in Response to Kisspeptin Agonist and Antagonist in Female Rhesus Monkeys (Macaca mulatta): Implication for the Mechanism of Puberty. Endocrinology 2012, 153, 825–836. [Google Scholar] [CrossRef]
- Capozzi, A.; Scambia, G.; Pontecorvi, A.; Lello, S. Hyperprolactinemia: Pathophysiology and therapeutic approach. Gynecol. Endocrinol. 2015, 31, 506–510. [Google Scholar] [CrossRef]
- Millar, R.P.; Sonigo, C.; Anderson, R.A.; George, J.; Maione, L.; Brailly-Tabard, S.; Chanson, P.; Binart, N.; Young, J. Hypothalamic-Pituitary-Ovarian Axis Reactivation by Kisspeptin-10 in Hyperprolactinemic Women with Chronic Amenorrhea. J. Endocr. Soc. 2017, 1, 1362–1371. [Google Scholar] [CrossRef]
- Ruohonen, S.T.; 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, 465–474. [Google Scholar] [CrossRef]
- Ricu, M.A.; Ramirez, V.D.; Paredes, A.H.; Lara, H.E. Evidence for a Celiac Ganglion-Ovarian Kisspeptin Neural Network in the Rat: Intraovarian Anti-Kisspeptin Delays Vaginal Opening and Alters Estrous Cyclicity. Endocrinology 2012, 153, 4966–4977. [Google Scholar] [CrossRef]
- Mondal, M.; Baruah, K.K.; Prakash, B.S. Determination of plasma kisspeptin concentrations during reproductive cycle and different phases of pregnancy in crossbred cows using bovine specific enzyme immunoassay. Gen. Comp. Endocrinol. 2015, 224, 168–175. [Google Scholar] [CrossRef] [PubMed]
- Mondal, M.; Karunakaran, M.; Baruah, K.K. Development and Validation of a Sensitive Enzymeimmunoassay for Determination of Plasma Metastin in Mithun (Bos frontalis ). J. Immunoass. Immunochem. 2016, 37, 201–216. [Google Scholar] [CrossRef] [PubMed]
- Yilmaz, S.A.; Kerimoglu, O.S.; Pekin, A.T.; Incesu, F.; Dogan, N.U.; Celik, C.; Unlu, A. Metastin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 2014, 180, 56–60. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Mo, Y.; Li, L.; Chen, Y.; Li, Y.; Yang, D. Increased plasma metastin levels in adolescent women with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 2010, 149, 72–76. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Tang, R.; Ding, X.; Zhu, J. Kisspeptin and Polycystic Ovary Syndrome. Front. Endocrinol. 2019, 10, 298. [Google Scholar] [CrossRef]
- Albalawi, F.S.; Daghestani, M.H.; Daghestani, M.H.; Eldali, A.; Warsy, A.S. rs4889 polymorphism in KISS1 gene, its effect on polycystic ovary syndrome development and anthropometric and hormonal parameters in Saudi women. J. Biomed. Sci. 2018, 25, 50. [Google Scholar] [CrossRef]
- Emekci Ozay, O.; Ozay, A.C.; Acar, B.; Cagliyan, E.; Seçil, M.; Küme, T. Role of kisspeptin in polycystic ovary syndrome (PCOS). Gynecol. Endocrinol. 2016, 32, 718–722. [Google Scholar] [CrossRef]
- Nikolettos, K.; Vlahos, N.; Pagonopoulou, O.; Nikolettos, N.; Zikopoulos, K.; Tsikouras, P.; Kontomanolis, E.; Damaskos, C.; Garmpis, N.; Asimakopoulos, B. Is There an Association Between Circulating Kisspeptin Levels and Ovarian Reserve in Women of Reproductive Age? In Vivo 2023, 37, 2219–2223. [Google Scholar] [CrossRef]
- Nyagolova, P.V.; Mitkov, M.D.; Orbetzova, M.M.; Terzieva, D.D. Kisspeptin and Galanin-like Peptide (GALP) Levels in Women with Polycystic Ovary Syndrome. Int. J. Pharmaceut. Med. Res. 2016, 4, 7–12. [Google Scholar]
- Jeon, Y.E.; Lee, K.E.; Jung, J.A.; Yim, S.Y.; Kim, H.; Seo, S.K.; Cho, S.; Choi, Y.S.; Lee, B.S. Kisspeptin, Leptin, and Retinol-Binding Protein 4 in Women with Polycystic Ovary Syndrome. Gynecol. Obstet. Investig. 2013, 75, 268–274. [Google Scholar] [CrossRef] [PubMed]
- Katulski, K.; Podfigurna, A.; Czyzyk, A.; Meczekalski, B.; Genazzani, A.D. Kisspeptin and LH pulsatile temporal coupling in PCOS patients. Endocrine 2018, 61, 149–157. [Google Scholar] [CrossRef] [PubMed]
- Collette, T. Evidence for an increased release of proteolytic activity by the eutopic endometrial tissue in women with endometriosis and for involvement of matrix metalloproteinase-9. Hum. Reprod. 2004, 19, 1257–1264. [Google Scholar] [CrossRef]
- Collette, T.; Maheux, R.; Mailloux, J.; Akoum, A. Increased expression of matrix metalloproteinase-9 in the eutopic endometrial tissue of women with endometriosis. Hum. Reprod. 2006, 21, 3059–3067. [Google Scholar] [CrossRef]
- Di Carlo, C.; Bonifacio, M.; Tommaselli, G.A.; Bifulco, G.; Guerra, G.; Nappi, C. Metalloproteinases, vascular endothelial growth factor, and angiopoietin 1 and 2 in eutopic and ectopic endometrium. Fertil. Steril. 2009, 91, 2315–2323. [Google Scholar] [CrossRef]
- Makri, A.; Msaouel, P.; Petraki, C.; Milingos, D.; Protopapas, A.; Liapi, A.; Antsaklis, A.; Magkou, C.; Koutsilieris, M. KISS1/KISS1R Expression in Eutopic and Ectopic Endometrium of Women Suffering from Endometriosis. In Vivo 2012, 26, 119–127. [Google Scholar]
- Kleimenova, T.; Polyakova, V.; Linkova, N.; Drobintseva, A.; Medvedev, D.; Krasichkov, A. The Expression of Kisspeptins and Matrix Metalloproteinases in Extragenital Endometriosis. Biomedicines 2024, 12, 94. [Google Scholar] [CrossRef]
- Abdelkareem, A.O.; Alotaibi, F.T.; AlKusayer, G.M.; Ait-Allah, A.S.; Rasheed, S.M.; Helmy, Y.A.; Allaire, C.; Peng, B.; Yong, P.J.; Bedaiwy, M.A. Immunoreactivity of Kisspeptin and Kisspeptin Receptor in Eutopic and Ectopic Endometrial Tissue of Women With and Without Endometriosis. Reprod. Sci. 2020, 27, 1731–1741. [Google Scholar] [CrossRef]
- Timologou, A.; Zafrakas, M.; Grimbizis, G.; Miliaras, D.; Kotronis, K.; Stamatopoulos, P.; Tarlatzis, B.C. Immunohistochemical expression pattern of metastasis suppressors KAI1 and KISS1 in endometriosis and normal endometrium. Eur. J. Obstet. Gynecol. Reprod. Biol. 2016, 199, 110–115. [Google Scholar] [CrossRef]
- Önal, M.; Karli, P.; Özdemir, A.Z.; Kocaman, A.; Katirci, Y.; Çoban, G.; Nakişli, G.K.; Civil, Y.; Avci, B. Serum kisspeptin levels in deep-infiltrating, ovarian, and superficial endometriosis: A prospective observational study. Medicine 2022, 101, e31529. [Google Scholar] [CrossRef]
- Akad, M.; Socolov, D.; Akad, F.; Covali, R.; Crauciuc, E.; Stan, C.; Stan, C.; Socolov, R. Treatments in Patients with Polycystic Ovary Syndrome and Effects on Kisspeptin Serum Levels. Maedica 2022, 17, 799–804. [Google Scholar] [CrossRef] [PubMed]
- Kaya, C.; Alay, İ.; Babayeva, G.; Gedikbaşı, A.; Ertaş Kaya, S.; Ekin, M.; Yaşar, L. Serum Kisspeptin levels in unexplained infertility, polycystic ovary syndrome, and male factor infertility. Gynecol. Endocrinol. Off. J. Int. Soc. Gynecol. Endocrinol. 2019, 35, 228–232. [Google Scholar] [CrossRef] [PubMed]
- Mumtaz, A.; Khalid, A.; Jamil, Z.; Fatima, S.S.; Arif, S.; Rehman, R. Kisspeptin: A Potential Factor for Unexplained Infertility and Impaired Embryo Implantation. Int. J. Fertil. Steril. 2017, 11, 99–104. [Google Scholar] [CrossRef] [PubMed]
- Podfigurna, A.; Szeliga, A.; Meczekalski, B. Serum kisspeptin and corticotropin-releasing hormone levels in patients with functional hypothalamic amenorrhea. Gynecol. Reprod. Endocrinol. Metab. 2020, 1, 37–42. [Google Scholar]
- Jayasena, C.N.; Nijher, G.M.K.; Chaudhri, O.B.; Murphy, K.G.; Ranger, A.; Lim, A.; Patel, D.; Mehta, A.; Todd, C.; Ramachandran, R.; 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, 4315–4323. [Google Scholar] [CrossRef]
- Castellano, J.M.; Navarro, V.M.; Fernández-Fernández, R.; Nogueiras, R.; Tovar, S.; Roa, J.; Vazquez, M.J.; Vigo, E.; Casanueva, F.F.; Aguilar, E.; et al. Changes in Hypothalamic KiSS-1 System and Restoration of Pubertal Activation of the Reproductive Axis by Kisspeptin in Undernutrition. Endocrinology 2005, 146, 3917–3925. [Google Scholar] [CrossRef]
- Hudson, A.D.; Kauffman, A.S. Metabolic actions of kisspeptin signaling: Effects on body weight, energy expenditure, and feeding. Pharmacol. Ther. 2022, 231, 107974. [Google Scholar] [CrossRef]
- Thomas, G.B.; Mercer, J.E.; Karalis, T.; Rao, A.; Cummins, J.T.; Clarke, I.J. Effect of Restricted Feeding on the Concentrations of Growth Hormone (GH), Gonadotropins, and Prolactin (PRL) in Plasma, and on the Amounts of Messenger Ribonucleic Acid for GH, Gonadotropin Subunits, and PRL in the Pituitary Glands of Adult Ovariectomized Ewes. Endocrinology 1990, 126, 1361–1367. [Google Scholar] [CrossRef]
- Seminara, S.B.; Dipietro, M.J.; Ramaswamy, S.; Crowley, W.F.; Plant, T.M. Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): A finding with therapeutic implications. Endocrinology 2006, 147, 2122–2126. [Google Scholar] [CrossRef]
- Zhai, J.; Liu, J.; Zhao, S.; Zhao, H.; Chen, Z.-J.; Du, Y.; Li, W. Kisspeptin-10 inhibits OHSS by suppressing VEGF secretion. Reproduction 2017, 154, 355–362. [Google Scholar] [CrossRef]
- Kotani, M.; Detheux, M.; Vandenbogaerde, A.; Communi, D.; Vanderwinden, J.-M.; Poul, E.L.; Brézillon, S.; Tyldesley, R.; Suarez-Huerta, N.; Vandeput, F.; 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, 34631–34636. [Google Scholar] [CrossRef] [PubMed]
- Wahab, F.; Atika, B.; Shahab, M.; Behr, R. Kisspeptin signalling in the physiology and pathophysiology of the urogenital system. Nat. Rev. Urol. 2016, 13, 21–32. [Google Scholar] [CrossRef] [PubMed]
- Pinto, F.M.; Cejudo-Román, A.; Ravina, C.G.; Fernández-Sánchez, M.; Martín-Lozano, D.; Illanes, M.; Tena-Sempere, M.; Candenas, M.L. Characterization of the kisspeptin system in human spermatozoa. Int. J. Androl. 2012, 35, 63–73. [Google Scholar] [CrossRef]
- Ramzan, M.H.; Ramzan, M.; Ramzan, F.; Wahab, F.; Jelani, M.; Khan, M.A.; Shah, M. Insight into the serum kisspeptin levels in infertile males. Arch. Iran. Med. 2015, 18, 12–17. [Google Scholar]
- Zou, P.; Wang, X.; Chen, Q.; Yang, H.; Zhou, N.; Sun, L.; Chen, H.; Liu, J.; Ao, L.; Cui, Z.; et al. Kisspeptin Protein in Seminal Plasma Is Positively Associated with Semen Quality: Results from the MARHCS Study in Chongqing, China. BioMed Res. Int. 2019, 2019, 5129263. [Google Scholar] [CrossRef]
- Selvaraj, S.; Ohga, H.; Nyuji, M.; Kitano, H.; Nagano, N.; Yamaguchi, A.; Matsuyama, M. Subcutaneous administration of Kiss1 pentadecapeptide accelerates spermatogenesis in prepubertal male chub mackerel (Scomber japonicus). Comp. Biochem. Physiol. A. Mol. Integr. Physiol. 2013, 166, 228–236. [Google Scholar] [CrossRef]
- Mei, H.; Doran, J.; Kyle, V.; Yeo, S.-H.; Colledge, W.H. Does Kisspeptin Signaling have a Role in the Testes? Front. Endocrinol. 2013, 4, 198. [Google Scholar] [CrossRef]
- Irfan, S.; Ehmcke, J.; Wahab, F.; Shahab, M.; Schlatt, S. Intratesticular action of kisspeptin in rhesus monkey ( Macaca mulatta ). Andrologia 2014, 46, 610–617. [Google Scholar] [CrossRef]
- Jayasena, C.N.; Nijher, G.M.K.; Comninos, A.N.; Abbara, A.; Januszewki, A.; Vaal, M.L.; Sriskandarajah, L.; Murphy, K.G.; Farzad, Z.; Ghatei, M.A.; et al. The Effects of Kisspeptin-10 on Reproductive Hormone Release Show Sexual Dimorphism in Humans. J. Clin. Endocrinol. Metab. 2011, 96, E1963–E1972. [Google Scholar] [CrossRef]
- Abbara, A.; Eng, P.C.; Phylactou, M.; Clarke, S.A.; Mills, E.; Chia, G.; Yang, L.; Izzi-Engbeaya, C.; Smith, N.; Jayasena, C.N.; et al. Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism. Neuroendocrinology 2021, 111, 1176–1186. [Google Scholar] [CrossRef]
- George, J.T.; Veldhuis, J.D.; Roseweir, A.K.; Newton, C.L.; Faccenda, E.; Millar, R.P.; Anderson, R.A. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J. Clin. Endocrinol. Metab. 2011, 96, E1228-36. [Google Scholar] [CrossRef] [PubMed]
- Cohlen, B.J.; te Velde, E.R.; Scheffer, G.; van Kooij, R.J.; Maria de Brouwer, C.P.; van Zonneveld, P. The pattern of the luteinizing hormone surge in spontaneous cycles is related to the probability of conception. Fertil. Steril. 1993, 60, 413–417. [Google Scholar] [CrossRef] [PubMed]
- Chan, Y.-M.; Lippincott, M.F.; Butler, J.P.; Sidhoum, V.F.; Li, C.X.; Plummer, L.; Seminara, S.B. Exogenous kisspeptin administration as a probe of GnRH neuronal function in patients with idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 2014, 99, E2762–E2771. [Google Scholar] [CrossRef] [PubMed]
- Chan, Y.-M.; Lippincott, M.F.; Sales Barroso, P.; Alleyn, C.; Brodsky, J.; Granados, H.; Roberts, S.A.; Sandler, C.; Srivatsa, A.; Seminara, S.B. Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay. J. Clin. Endocrinol. Metab. 2020, 105, e2717–e2725. [Google Scholar] [CrossRef]
- Abbara, A.; Narayanaswamy, S.; Izzi-Engbeaya, C.; Comninos, A.N.; Clarke, S.A.; Malik, Z.; Papadopoulou, D.; Clobentz, A.; Sarang, Z.; Bassett, P.; et al. Hypothalamic Response to Kisspeptin-54 and Pituitary Response to Gonadotropin-Releasing Hormone Are Preserved in Healthy Older Men. Neuroendocrinology 2018, 106, 401–410. [Google Scholar] [CrossRef]
- Jayasena, C.N.; Comninos, A.N.; Veldhuis, J.D.; Misra, S.; Abbara, A.; Izzi-Engbeaya, C.; Donaldson, M.; Ghatei, M.A.; Bloom, S.R.; Dhillo, W.S. A single injection of kisspeptin-54 temporarily increases luteinizing hormone pulsatility in healthy women. Clin. Endocrinol. 2013, 79, 558–563. [Google Scholar] [CrossRef]
- Abbara, A.; Ratnasabapathy, R.; Jayasena, C.N.; Dhillo, W.S. The effects of kisspeptin on gonadotropin release in non-human mammals. Adv. Exp. Med. Biol. 2013, 784, 63–87. [Google Scholar] [CrossRef]
- Dhillo, W.S.; Chaudhri, O.B.; Thompson, E.L.; Murphy, K.G.; Patterson, M.; Ramachandran, R.; Nijher, G.K.; Amber, V.; Kokkinos, A.; Donaldson, M.; et al. Kisspeptin-54 Stimulates Gonadotropin Release Most Potently during the Preovulatory Phase of the Menstrual Cycle in Women. J. Clin. Endocrinol. Metab. 2007, 92, 3958–3966. [Google Scholar] [CrossRef]
- Jayasena, C.N.; Abbara, A.; Comninos, A.N.; Nijher, G.M.K.; Christopoulos, G.; Narayanaswamy, S.; Izzi-Engbeaya, C.; Sridharan, M.; Mason, A.J.; Warwick, J.; et al. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. J. Clin. Investig. 2014, 124, 3667–3677. [Google Scholar] [CrossRef]
- Abbara, A.; Clarke, S.A.; Dhillo, W.S. Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment. Endocr. Rev. 2018, 39, 593–628. [Google Scholar] [CrossRef]
- Garcia-Ortega, J.; Pinto, F.M.; Fernandez-Sanchez, M.; Prados, N.; Cejudo-Roman, A.; Almeida, T.A.; Hernandez, M.; Romero, M.; Tena-Sempere, M.; Candenas, L. Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells. Hum. Reprod. 2014, 29, 2736–2746. [Google Scholar] [CrossRef] [PubMed]
- Abbara, A.; Jayasena, C.N.; Christopoulos, G.; Narayanaswamy, S.; Izzi-Engbeaya, C.; Nijher, G.M.K.; Comninos, A.N.; Peters, D.; Buckley, A.; Ratnasabapathy, R.; et al. Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy. J. Clin. Endocrinol. Metab. 2015, 100, 3322–3331. [Google Scholar] [CrossRef]
- Abbara, A.; Clarke, S.; Islam, R.; Izzi-Engbeaya, C.; Ratnasabapathy, R.; Nesbitt, A.; Vimalesvaran, S.; Salim, R.; Lavery, S.A.; Bloom, S.R.; 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, 1915–1924. [Google Scholar] [CrossRef] [PubMed]
- Abbara, A.; Ufer, M.; Voors-Pette, C.; Berman, L.; Ezzati, M.; Wu, R.; Lee, T.-Y.; Ferreira, J.C.A.; Migoya, E.; Dhillo, W.S. Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: Results from 2 randomized, placebo-controlled clinical tricals. Fertil. Steril. 2024, 121, 95–106. [Google Scholar] [CrossRef] [PubMed]
- Abbara, A.; Islam, R.; Clarke, S.A.; Jeffers, L.; Christopoulos, G.; Comninos, A.N.; Salim, R.; Lavery, S.A.; Vuong, T.N.L.; Humaidan, P.; et al. Clinical parameters of ovarian hyperstimulation syndrome following different hormonal triggers of oocyte maturation in IVF treatment. Clin. Endocrinol. 2018, 88, 920–927. [Google Scholar] [CrossRef]
- Abbara, A.; Hunjan, T.; Ho, V.N.A.; Clarke, S.A.; Comninos, A.N.; Izzi-Engbeaya, C.; Ho, T.M.; Trew, G.H.; Hramyka, A.; Kelsey, T.; et al. Endocrine Requirements for Oocyte Maturation Following hCG, GnRH Agonist, and Kisspeptin During IVF Treatment. Front. Endocrinol. 2020, 11, 537205. [Google Scholar] [CrossRef]
- Saadeldin, I.M.; Koo, O.J.; Kang, J.T.; Kwon, D.K.; Park, S.J.; Kim, S.J.; Moon, J.H.; Oh, H.J.; Jang, G.; Lee, B.C. Paradoxical effects of kisspeptin: It enhances oocyte in vitro maturation but has an adverse impact on hatched blastocysts during in vitro culture. Reprod. Fertil. Dev. 2012, 24, 656–668. [Google Scholar] [CrossRef]
- Ebrahimi, B.; Valojerdi, M.R.; Eftekhari-Yazdi, P.; Baharvand, H.; Farrokhi, A. IVM and gene expression of sheep cumulus–oocyte complexes following different methods of vitrification. Reprod. Biomed. Online 2010, 20, 26–34. [Google Scholar] [CrossRef]
- Choi, J.; Lee, J.-Y.; Lee, E.; Yoon, B.-K.; Bae, D.; Choi, D. Cryopreservation of the mouse ovary inhibits the onset of primordial follicle development. Cryobiology 2007, 54, 55–62. [Google Scholar] [CrossRef]
- Hameed, S.; Jayasena, C.N.; Dhillo, W.S. Kisspeptin and fertility. J. Endocrinol. 2011, 208, 97–105. [Google Scholar] [CrossRef]
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Kotanidou, S.; Nikolettos, N.; Kritsotaki, N.; Tsikouras, P.; Tiptiri-Kourpeti, A.; Nikolettos, K. Kisspeptins Regulating Fertility: Potential Future Therapeutic Approach in Infertility Treatment. J. Clin. Med. 2025, 14, 3284. https://doi.org/10.3390/jcm14103284
Kotanidou S, Nikolettos N, Kritsotaki N, Tsikouras P, Tiptiri-Kourpeti A, Nikolettos K. Kisspeptins Regulating Fertility: Potential Future Therapeutic Approach in Infertility Treatment. Journal of Clinical Medicine. 2025; 14(10):3284. https://doi.org/10.3390/jcm14103284
Chicago/Turabian StyleKotanidou, Sonia, Nikos Nikolettos, Nektaria Kritsotaki, Panagiotis Tsikouras, Angeliki Tiptiri-Kourpeti, and Konstantinos Nikolettos. 2025. "Kisspeptins Regulating Fertility: Potential Future Therapeutic Approach in Infertility Treatment" Journal of Clinical Medicine 14, no. 10: 3284. https://doi.org/10.3390/jcm14103284
APA StyleKotanidou, S., Nikolettos, N., Kritsotaki, N., Tsikouras, P., Tiptiri-Kourpeti, A., & Nikolettos, K. (2025). Kisspeptins Regulating Fertility: Potential Future Therapeutic Approach in Infertility Treatment. Journal of Clinical Medicine, 14(10), 3284. https://doi.org/10.3390/jcm14103284