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Investigation of the relationship between prolactin and infertility by expression levels of kisspeptin (KISS1), KISS1 receptor, neurokinin (NK), NK receptor genes

Year 2024, EARLY ONLINE, 1 - 8
https://doi.org/10.18621/eurj.1479432

Abstract

Objectives: Prolactin level, which rises in the blood during pregnancy and after birth, plays a role in physiological events such as metabolism and reproduction. Increased blood levels of prolactin lead to various disorders. The most important of these are amenorrhea/galactorrhea and disruption of ovulation. Disruption of ovulation is a serious problem and can lead to infertility problems. Kisspeptin (KISS1) and Neurokinins are involved in the control of ovulation. This study aimed to explain the relationship between Prolactin and infertility with the expression levels of KISS1, KISS1 Receptor (KISS1R), Neurokinin (NK), Neurokinin Receptor (NKR) genes.

Methods: Fourty female Wistar Albino rats, 12-16 weeks old, were used in this study. Three groups were formed, 10 rats were in Group-1 as Control, 10 rats were in Group-2 given Saline, and 20 rats were in Group-3 given Metoclopramide (Metpamid, Sifar, Turkey). The raising effect of Metoclopramide on blood Prolactin levels leading to infertility was helpful to clarify the process in comparison with the other two groups not given Metoclopramide.

Results: In Group-3 given Metoclopramide, the blood Prolactin levels were found to be significantly higher compared to Group-1 and Group-2 subjects that were not given this drug. Expression values of KISS1, KISS1R and NK, NKR genes were found to be significantly decreased in Group-3, where the Prolactin level increased, compared to the other two groups (P<0.001).

Conclusions: In this study, it has been shown that the expression levels of Neuropeptide genes (KISS1, NK) are suppressed with the direct effect of hyperprolactinemia, thus decreasing the amount and functions of Neuropeptides. In our study it was concluded that the negative effects of prolactin elevation on reproduction may be mediated by neuropeptides.

Ethical Statement

The use of experimental animals in this study was allowed and recorded with reference decision number 1 approved in the 8th session of the local ethics academic authority named Çukurova University Medical Faculty Experimental Research and Application Center dated 21 August 2013. The animals were carefully treated in accordance with the guidelines confirmed by this official permission.

Supporting Institution

Çukurova University

References

  • 1. World Health Organization, https://www.who.int/news/item/04-04-2023-1-in-6-people-globally-affected-by-infertility, Avaiable Date:26.07.2023.
  • 2. Mahzari M, Alhamlan KS, Alhussaini NA, et al. Epidemiological and clinical profiles of Saudi patients with hyperprolactinemia in a single tertiary care center. Ann Saudi Med. 2022;42(5):334-342. doi: 10.5144/0256-4947.2022.334.
  • 3. Searle L, McDowell S, Willink R, Krebs J. A cannulated prolactin series reduces the need for further investigations in women with infertility and lowers the number of false positive screening prolactin measurements. Aust N Z J Obstet Gynaecol. 2021;61(6):949-954. doi: 10.1111/ajo.13416.
  • 4. Spaziani M, Tarantino C, Tahani N, et al. Hypothalamo-Pituitary axis and puberty. Mol Cell Endocrinol. 2021;520:111094. doi: 10.1016/j.mce.2020.111094.
  • 5. Luan X, Yu H, Wei X, et al. GPR54 polymorphisms in Chinese girls with central precocious puberty. Neuroendocrinology. 2007;86(2):77-83. doi: 10.1159/000107511.
  • 6. Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev. 2009;30(6):713-743. doi: 10.1210/er.2009-0005.
  • 7. Kotani M, Detheux M, Vandenbogaerde A, 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(37):34631-34636. doi: 10.1074/jbc.M104847200.
  • 8. Ohtaki T, Shintani Y, Honda S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411(6837):613-617. doi: 10.1038/35079135.
  • 9. Roseweir AK, Millar RP. The role of kisspeptin in the control of gonadotrophin secretion. Hum Reprod Update. 2009;15(2):203-212. doi: 10.1093/humupd/dmn058.
  • 10. Lehman MN, Coolen LM, Goodman RL. 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(8):3479-3489. doi: 10.1210/en.2010-0022.
  • 11. Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology. 2010;151(1):301-311. doi: 10.1210/en.2009-0541.
  • 12. Sonigo C, Bouilly J, Carré N, et al. Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration. J Clin Invest. 2012;122(10):3791-3795. doi: 10.1172/JCI63937.
  • 13. Fourman LT, Fazeli PK. Neuroendocrine causes of amenorrhea--an update. J Clin Endocrinol Metab. 2015;100(3):812-824. doi: 10.1210/jc.2014-3344.
  • 14. Horseman ND, Zhao W, Montecino-Rodriguez E, et al. Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J. 1997;16(23):6926-6935. doi: 10.1093/emboj/16.23.6926.
  • 15. Ormandy CJ, Camus A, Barra J, et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev. 1997;11(2):167-178. doi: 10.1101/gad.11.2.167.
  • 16. Ladyman SR, Hackwell ECR, Brown RSE. The role of prolactin in co-ordinating fertility and metabolic adaptations during reproduction. Neuropharmacology. 2020;167:107911. doi: 10.1016/j.neuropharm.2019.107911.
  • 17. Iancu ME, Albu AI, Albu DN. Prolactin Relationship with Fertility and In Vitro Fertilization Outcomes-A Review of the Literature. Pharmaceuticals (Basel). 2023;16(1):122. doi: 10.3390/ph16010122.
  • 18. Iwata K, Kunimura Y, Ozawa H. Hypothalamic Kisspeptin Expression in Hyperandrogenic Female Rats and Aging Rats. Acta Histochem Cytochem. 2019;52(5):85-91. doi: 10.1267/ahc.19013.
  • 19. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100(19):10972-10976. doi: 10.1073/pnas.1834399100.
  • 20. Topaloglu AK, Tello JA, Kotan LD, et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med. 2012;366(7):629-635. doi: 10.1056/NEJMoa1111184.
  • 21. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012;92(3):1235-1316. doi: 10.1152/physrev.00037.2010.
  • 22. Han SK, Gottsch ML, Lee KJ, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005;25(49):11349-11356. doi: 10.1523/JNEUROSCI.3328-05.2005.
Year 2024, EARLY ONLINE, 1 - 8
https://doi.org/10.18621/eurj.1479432

Abstract

References

  • 1. World Health Organization, https://www.who.int/news/item/04-04-2023-1-in-6-people-globally-affected-by-infertility, Avaiable Date:26.07.2023.
  • 2. Mahzari M, Alhamlan KS, Alhussaini NA, et al. Epidemiological and clinical profiles of Saudi patients with hyperprolactinemia in a single tertiary care center. Ann Saudi Med. 2022;42(5):334-342. doi: 10.5144/0256-4947.2022.334.
  • 3. Searle L, McDowell S, Willink R, Krebs J. A cannulated prolactin series reduces the need for further investigations in women with infertility and lowers the number of false positive screening prolactin measurements. Aust N Z J Obstet Gynaecol. 2021;61(6):949-954. doi: 10.1111/ajo.13416.
  • 4. Spaziani M, Tarantino C, Tahani N, et al. Hypothalamo-Pituitary axis and puberty. Mol Cell Endocrinol. 2021;520:111094. doi: 10.1016/j.mce.2020.111094.
  • 5. Luan X, Yu H, Wei X, et al. GPR54 polymorphisms in Chinese girls with central precocious puberty. Neuroendocrinology. 2007;86(2):77-83. doi: 10.1159/000107511.
  • 6. Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev. 2009;30(6):713-743. doi: 10.1210/er.2009-0005.
  • 7. Kotani M, Detheux M, Vandenbogaerde A, 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(37):34631-34636. doi: 10.1074/jbc.M104847200.
  • 8. Ohtaki T, Shintani Y, Honda S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411(6837):613-617. doi: 10.1038/35079135.
  • 9. Roseweir AK, Millar RP. The role of kisspeptin in the control of gonadotrophin secretion. Hum Reprod Update. 2009;15(2):203-212. doi: 10.1093/humupd/dmn058.
  • 10. Lehman MN, Coolen LM, Goodman RL. 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(8):3479-3489. doi: 10.1210/en.2010-0022.
  • 11. Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology. 2010;151(1):301-311. doi: 10.1210/en.2009-0541.
  • 12. Sonigo C, Bouilly J, Carré N, et al. Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration. J Clin Invest. 2012;122(10):3791-3795. doi: 10.1172/JCI63937.
  • 13. Fourman LT, Fazeli PK. Neuroendocrine causes of amenorrhea--an update. J Clin Endocrinol Metab. 2015;100(3):812-824. doi: 10.1210/jc.2014-3344.
  • 14. Horseman ND, Zhao W, Montecino-Rodriguez E, et al. Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J. 1997;16(23):6926-6935. doi: 10.1093/emboj/16.23.6926.
  • 15. Ormandy CJ, Camus A, Barra J, et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev. 1997;11(2):167-178. doi: 10.1101/gad.11.2.167.
  • 16. Ladyman SR, Hackwell ECR, Brown RSE. The role of prolactin in co-ordinating fertility and metabolic adaptations during reproduction. Neuropharmacology. 2020;167:107911. doi: 10.1016/j.neuropharm.2019.107911.
  • 17. Iancu ME, Albu AI, Albu DN. Prolactin Relationship with Fertility and In Vitro Fertilization Outcomes-A Review of the Literature. Pharmaceuticals (Basel). 2023;16(1):122. doi: 10.3390/ph16010122.
  • 18. Iwata K, Kunimura Y, Ozawa H. Hypothalamic Kisspeptin Expression in Hyperandrogenic Female Rats and Aging Rats. Acta Histochem Cytochem. 2019;52(5):85-91. doi: 10.1267/ahc.19013.
  • 19. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100(19):10972-10976. doi: 10.1073/pnas.1834399100.
  • 20. Topaloglu AK, Tello JA, Kotan LD, et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med. 2012;366(7):629-635. doi: 10.1056/NEJMoa1111184.
  • 21. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012;92(3):1235-1316. doi: 10.1152/physrev.00037.2010.
  • 22. Han SK, Gottsch ML, Lee KJ, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005;25(49):11349-11356. doi: 10.1523/JNEUROSCI.3328-05.2005.
There are 22 citations in total.

Details

Primary Language English
Subjects Gene Expression
Journal Section Original Articles
Authors

Eylül Akbal 0000-0001-5630-9056

Mehmet Bertan Yılmaz 0000-0001-5558-3299

Early Pub Date August 22, 2024
Publication Date
Submission Date May 9, 2024
Acceptance Date August 10, 2024
Published in Issue Year 2024 EARLY ONLINE

Cite

AMA Akbal E, Yılmaz MB. Investigation of the relationship between prolactin and infertility by expression levels of kisspeptin (KISS1), KISS1 receptor, neurokinin (NK), NK receptor genes. Eur Res J. Published online August 1, 2024:1-8. doi:10.18621/eurj.1479432

e-ISSN: 2149-3189 


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