The role of kisspeptin in female and male reproduction

Öz

Kisspeptin is a neuropeptide responsible for controlling the synthesis of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The G-protein-coupled receptor 54/kisspeptin 1 receptor (GPR54/KISS1R) is involved in its action. The comprehension of kisspeptin and its actions represents a significant breakthrough in the field of reproductive biology. Kisspeptins play a crucial role in the development and optimal functioning of the reproductive system in both female and male. Additionally, it contributes to the onset of puberty, regulating feedback processes, and influencing sexual desire and arousal. It regulates a number of reproductive functions in women, including ovulation, lactation, ovarian development, follicle development, oocyte maturation, and pregnancy via the hypothalamic-pituitary-gonadal (HPG) axis. Spermatogenesis, sperm function, Leydig cells, and reproductive behaviour are all impacted by it in men. Infertility and polycystic ovarian syndrome (PCOS) are among the diseases linked to kisspeptin dysregulation, according to the research. For potential future use in diagnosing and treating problems, it may be helpful to understand the mechanisms behind kisspeptin's effects on the reproductive system. This review focuses on the regulatory function of kisspeptin on the HPG axis and the impact of kisspeptin on reproductive processes in both female and male.

Anahtar Kelimeler

• Kisspeptin
• HPG axis
• Reproduction
• Infertility

Dişi ve erkek üreme sisteminde kisspeptinin rolü

Öz

Kisspeptin, gonadotropin salgılatıcı hormon (GnRH), lüteinizan hormon (LH) ve folikül uyarıcı hormon (FSH) sentezini kontrol etmekten sorumlu bir nöropeptittir. Etkilerini G-protein-bağlı reseptör 54/kisspeptin 1 reseptörü (GPR54/KISS1R) olarak bilinen G-protein-bağlı bir reseptör aracılığıyla gösterir. Kisspeptin ve etkilerinin anlaşılması, üreme biyolojisi alanında önemli bir atılımı temsil etmektedir. Kisspeptinler hem erkeklerde hem de kadınlarda üreme sisteminin gelişiminde ve optimal işleyişinde çok önemli bir rol oynamaktadır. Ayrıca ergenliğin başlamasında, geri bildirim süreçlerinin düzenlenmesinde ve cinsel istek ve uyarılmayı etkilemede rol oynar. Kadın üreme sisteminde, HPG ekseni aracılığıyla gebelik, emzirme, yumurtalık gelişimi, folikül gelişimi, oosit olgunlaşması ve yumurtlama gibi çeşitli süreçleri kontrol eder. Erkek üreme sisteminde ise Leydig hücreleri, spermatogenez, sperm fonksiyonu ve üreme davranışının düzenlenmesinde rol oynar. Araştırmalar, polikistik over sendromu (PCOS) ve infertilite gibi durumlarda kisspeptin düzensizliğinin patojenik önemini ortaya koymuştur. Kisspeptinin üreme ekseni üzerindeki etkisi ve ilişkili mekanizmaları hakkında fikir edinmek, kisspeptinin gelecekte hastalıkların tanı ve tedavisinde kullanılmasını kolaylaştıracaktır. Bu derleme, kisspeptinin hipotalamik-hipofiz-gonadal (HPG) eksen üzerindeki düzenleyici işlevine ve kisspeptinin hem kadınlarda hem de erkeklerde üreme süreçleri üzerindeki etkisine odaklanmaktadır.

Anahtar Kelimeler

• Kisspeptin
• HPG ekseni
• Üreme
• İnfertilite

Kaynakça

1. Baba, T., Kang, H.S., Hosoe, Y., Kharma, B., Abiko, K., Matsumura, N., ... & Konishi, I. (2015). Menstrual cyclic change of metastin/GPR54 in endometrium. Medical Molecular Morphology, 48, 76-84.
2. Cao, Y., Li, Z., Jiang, W., Ling, Y. & Kuang, H. (2019). Reproductive functions of Kisspeptin/KISS1R Systems in the Periphery. Reproductive Biology and Endocrinology, 17(1), 65.
3. Caraty, A., Smith, J.T., Lomet, D., Ben Saïd, S., Morrissey, A., Cognie, J., ... & Clarke, I. J. (2007). Kisspeptin synchronizes preovulatory surges in cyclical ewes and causes ovulation in seasonally acyclic ewes. Endocrinology, 148(11), 5258–5267.
4. Chanson, P. & Maiter, D. (2019). The epidemiology, diagnosis and treatment of Prolactinomas: The old and the new. Best Practice & Research Clinical Endocrinology & Metabolism, 33(2), 101290.
5. Chakravarthi, V.P., Ghosh, S., Housami, S.M., Wang, H., Roby, K.F., Wolfe, M.W., ... & Rumi M.A.K. (2021). ERβ regulated ovarian kisspeptin plays an important role in oocyte maturation. Molecular and Cellular Endocrinology, 527, 111208.
6. Chianese, R., Ciaramella, V., Fasano, S., Pierantoni, R. & Meccariello, R. (2017). Kisspeptin regulates steroidogenesis and spermiation in anuran amphibian. Reproduction, 154(4), 403-414.
7. Chianese, R., Cobellis, G., Chioccarelli, T., Ciaramella, V., Migliaccio, M., Fasano, S. ... & Meccariello, R. (2016). Kisspeptins, Estrogens and Male Fertility. Current Medicinal Chemistry, 23(36), 4070-4091.
8. Chianese, R., Ciaramella, V., Fasano, S., Pierantoni, R. & Meccariello, R. (2015). Kisspeptin drives germ cell progression in the anuran amphibian Pelophylax esculentus: a study carried out in ex vivo testes. General and Comparative Endocrinology, 211, 81-91.

9. Chianese, R., Ciaramella, V., Fasano, S., Pierantoni, R. & Meccariello, R. (2013). Kisspeptin receptor, GPR54, as a candidate for the regulation of testicular activity in the frog Rana esculenta. Biology of Reproduction, 88(3), 73.
10. Clarkson, J. & Herbison, A.E. (2006). Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology, 147(12), 5817-25.
11. Dewailly, D., Andersen, C.Y., Balen, A., Broekmans, F., Dilaver, N., Fanchin, R., ... & Anderson, R.A. (2014). The physiology and clinical utility of anti-Mullerian hormone in women. Human Reproduction Update, 20(3), 370-85.
12. Fernandois, D., Na, E., Cuevas, F., Cruz, G., Lara, H.E. & Paredes, A.H. (2016). Kisspeptin is involved in ovarian follicular development during aging in rats. Journal of Endocrinology, 228(3), 161-70.
13. Fleming, R. (2020). Anti-Müllerian Hormone: A Personal View of the Empowering Analyte. Journal of Human Reproductive Sciences, 13(4), 257-260.
14. Gaytán, F., Gaytán, M., Castellano, J.M., Romero, M., Roa, J., Aparicio, B., ... & Tena-Sempere, M. (2009). KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction. American Journal of Physiology - Endocrinology and Metabolism, 296(3), 520-31.
15. Gaytan, F., Garcia-Galiano, D., Dorfman, M.D., Manfredi-Lozano, M., Castellano, J.M., Dissen, G.A., ... & Tena-Sempere, M. (2014). Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. Endocrinology, 155(8), 3088-97.
16. Gloria, A., Contri, A., Mele, E., Fasano, S., Pierantoni, R. & Meccariello, R. (2021). Kisspeptin Receptor on the Sperm Surface Reflects Epididymal Maturation in the Dog. International Journal of Molecular Sciences, 22(18), 10120.
17. Goto, T., Hirabayashi, M., Watanabe, Y., Sanbo, M., Tomita, K., Inoue, N., ... & Uenoyama, Y. (2020). Testosterone Supplementation Rescues Spermatogenesis and In Vitro Fertilizing Ability of Sperm in Kiss1 Knockout Mice. Endocrinology, 161(9), bqaa092.
18. Gottsch, M.L., Cunningham, M.J., Smith, J.T., Popa, S.M., Acohido, B.V., Crowley, W.F., ... & Steiner, R.A. (2004). A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology, 145(9), 4073-7.
19. Harter, C.J.L., Kavanagh, G.S. & Smith, J.T. (2018). The role of kisspeptin neurons in reproduction and metabolism. Journal of Endocrinology, 238(3), R173-R183.
20. Hu, K.L., Zhao, H., Chang, H.M., Yu, Y. & Qiao, J. (2018). Kisspeptin/Kisspeptin Receptor System in the Ovary. Frontiers in Endocrinology (Lausanne), 8, 365.
21. Hsu, M.C., Wang, J.Y., Lee, Y.J., Jong, D.S., Tsui, K.H. & Chiu, C.H. (2014). Kisspeptin modulates fertilization capacity of mouse spermatozoa. Reproduction, 147(6), 835-45.
22. Kotani, M., Katagiri, F., Hirai, T. & Kagawa, J. (2014). Plasma kisspeptin levels in male cases with hypogonadism. Endocrine Journal, 61(11), 1137-40.
23. Kotani, M., Detheux, M., Vandenbogaerde, A., Communi, D., Vanderwinden, J.M., Poul, E.L., ... & Parmentier, M. (2001). The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. The Journal of Biological Chemistry, 276(37), 34631-34636.
24. Lee, J.H., Miele, M.E., Hicks, D.J., Phillips, K.K., Trent, J.M., Weissman, B.E. & Welch, D.R. (1996). KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. Journal of the National Cancer Institute, 88(23), 1731-1737.
25. León, S., Barroso, A., Vázquez, M.J., García-Galiano, D., Manfredi-Lozano, M., Ruiz-Pino, F., ... & Tena-Sempere, M. (2016). Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity. Scientific Reports, 6,19206.
26. McNatty, K.P., Juengel, J.L., Reader, K.L., Lun, S., Myllymaa, S., Lawrence, S.B. ... & Laitinen, M.P.E. (2005). Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function. Reproduction, 129(4), 473-80.
27. Matsui, H., Takatsu, Y., Kumano, S., Matsumoto, H. & Ohtaki, T. (2004). Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochemical and Biophysical Research Communications, 320(2), 383-388.
28. Meccariello, R., Fasano, S. & Pierantoni, R. (2020). Kisspeptins, new local modulators of male reproduction: A comparative overview. General and Comparative Endocrinology, 299, 113618.
29. Mele, E., D'Auria, R., Scafuro, M., Marino, M., Fasano, S., Viggiano, A., ... & Meccariello, R. (2022). Differential Expression of Kisspeptin System and Kisspeptin Receptor Trafficking during Spermatozoa Transit in the Epididymis. Genes (Basel), 13(2), 295.
30. Muir, A.I., Chamberlain, L., Elshourbagy, N.A., Michalovich, D., Moore, D.J., Calamari, A., ... & Harrison, D.C. (2001). AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. The Journal of Biological Chemistry, 276, 28969-75.
31. Mottershead, D.G., Ritter, L.J. & Gilchrist, R.B. (2012). Signalling pathways mediating specific synergistic interactions between GDF9 and BMP15. Molecular Human Reproduction, 18(3), 121-128.
32. Nimri, R., Lebenthal, Y., Lazar, L., Chevrier, L., Phillip, M., Bar, M., ... & Gat-Yablonski, G. (2011). A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. The Journal of Clinical Endocrinology & Metabolism, 96(3), E536–E545.
33. Ohtaki, T., Shintani, Y., Honda, S., Matsumoto, H., Hori, A., Kanehashi, K., ... & Fujino, M. (2001). Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature, 411(6837), 613-617.
34. Owen, C.M., Zhou, X., Bernard, D.J. & Jaffe, L.A. (2021). Kisspeptin-54 injection induces a physiological luteinizing hormone surge and ovulation in mice. Biology of Reproduction, 104(6), 1181-1183.
35. Persani, L., Rossetti, R., Di Pasquale, E., Cacciatore, C. & Fabre, S. (2014). The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders. Human Reproduction Update, 20(6), 869-883.
36. Petrucci, L., Maranesi, M., Verini Supplizi, A., Dall'Aglio, C., Mandara, M.T., Quassinti, L., ... & Zerani, M. (2020). Kisspeptin/GnRH1 system in Leydig cells of horse (Equus caballus): Presence and function. Theriogenology, 152, 1-7.
37. Pinto, F.M., Cejudo-Román, A., Ravina, C.G., Fernández-Sánchez, M., Martín-Lozano, D., Illanes, M., ... & Candenas, M.L. (2012). Characterization of the kisspeptin system in human spermatozoa. International Journal of Andrology, 35(1), 63-73.
38. Ramzan, M.H., Ramzan, M., Ramzan, F., Wahab, F., Jelani, M., Khan, M.A. & Shah, M. (2015). Insight into the serum kisspeptin levels in infertile males. Archives of Iranian Medicine, 18(1), 12-17.
39. Ramzan, F. & Qureshi, I.Z. (2011). Intraperitoneal kisspeptin-10 administration induces dose-dependent degenerative changes in maturing rat testes. Life Sciences, 88(5-6), 246-256.
40. Saadeldin, I.M., Koo, O.J., Kang, J.T., Kwon, D., Park, S.J., Kim, S., ... & Lee, B.C. (2012). Paradoxical effects of kisspeptin: it enhances oocyte in vitro maturation but has an adverse impact on hatched blastocysts during in vitro culture. Reproduction Fertility and Development, 24(5), 656-668.
41. Seminara, S.B., Dipietro, M.J., Ramaswamy, S., Crowley Jr, W.F. & Plant, T.M. (2006). 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, 147(5), 2122-2126.
42. Seminara, S.B., Messager, S., Chatzidaki, E.E., Thresher, R.R., Acierno, J.S.Jr., Shagoury, J.K., ... & Colledge, W.H. (2003). The GPR54 gene as a regulator of puberty. The New England Journal of Medicine, 349(17), 1614-27.
43. Semple, R.K., Achermann, J.C., Ellery, J., Farooqi, I.S., Karet, F.E., Stanhope, R.G., ... & Aparicio, S.A. (2005). Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. The Journal of Clinical Endocrinology and Metabolism, 90(3), 1849-1855.
44. Sharma, A., Thaventhiran, T., Minhas, S., Dhillo, W.S. & Jayasena, C.N. (2020). Kisspeptin and Testicular Function-Is it Necessary? International Journal of Molecular Sciences, 21(8), 2958.
45. Sirois, J., Sayasith, K., Brown, K.A., Stock, A.E., Bouchard, N. & Doré, M. (2004). Cyclooxygenase-2 and its role in ovulation: a 2004 account. Human Reproduction Update, 10(5), 373-85.
46. Trevisan, C.M., Montagna, E., de Oliveira, R., Christofolini, D.M., Barbosa, C.P., Crandall, K.A. & Bianco, B. (2018). Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction? Cellular Physiology and Biochemistry, 49(4), 1259-1276.
47. Toolee, H., Rastegar, T., Solhjoo, S., Mortezaee, K., Mohammadipour, M., Kashani, R.R. & Akbari, M. (2019). Roles for Kisspeptin in proliferation and differentiation of spermatogonial cells isolated from mice offspring when the cells are cocultured with somatic cells. Journal of Cellular Biochemistry, 120(4), 5042-5054.
48. Zeydabadi Nejad, S., Ramezani Tehrani, F. & Zadeh-Vakili, A. (2017). The Role of Kisspeptin in Female Reproduction. International Journal of Endocrinology and Metabolism, 15(3), e44337.
49. Zou, P., Wang, X., Chen, Q., Yang, H., Zhou, N., Sun, L., ... & Cao, J. (2019). Kisspeptin Protein in Seminal Plasma Is Positively Associated with Semen Quality: Results from the MARHCS Study in Chongqing, China. BioMed Research International, 2019, 5129263.
50. Wu, S., Zhang, H., Tian, J., Liu, L., Dong, Y. & Mao, T. (2014). Expression of kisspeptin/GPR54 and PIBF/PR in the first trimester trophoblast and decidua of women with recurrent spontaneous abortion. Pathology - Research and Practice, 210(1), 47-54.