Skip to main content
Log in

Altered expression of the kisspeptin/KISS1R and neurokinin B/NK3R systems in mural granulosa and cumulus cells of patients with polycystic ovarian syndrome

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The neurokinin B (NKB)/NK3 receptor (NK3R) and kisspeptin (KISS1)/kisspeptin receptor (KISS1R), two systems essential for reproduction, are present in human granulosa cells (GCs) of healthy women and contribute to the control of fertility, at least partially, by acting on the gonads. However, little is known about the expression of these systems in GCs of women with polycystic ovarian syndrome (PCOS). The aim of this study was to analyze the expression of NKB/NK3R and KISS1/KISS1R in mural granulosa (MGCs) and cumulus cells (CCs) of PCOS women.

Methods

A cross-sectional study was performed in 46 healthy women and 43 PCOS women undergoing controlled ovarian stimulation. MGCs and CCs were collected from pre-ovulatory follicles after transvaginal ultrasound-guided oocyte retrieval and the expression of the genes encoding NKB (TAC3), NK3R (TACR3), KISS1, and its receptor (KISS1R) was analyzed using real-time quantitative RT-PCR.

Results

TAC3, TACR3, and KISS1 mRNA levels were decreased in MGCs and CCs of PCOS women. TAC3 positively correlated with KISS1 in MGCs of healthy women and TACR3 was positively associated with KISS1R in CCs from healthy women. These associations were not observed in PCOS women.

Conclusion

The NKB/NK3R and KISS1/KISS1R systems are dysregulated in MGCs and CCs of PCOS women. The lower expression of these systems in GCs could contribute to the abnormal follicle development and defective ovulation that characterize the pathogenesis of PCOS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370:685–97.

    Article  CAS  PubMed  Google Scholar 

  2. Livadas S, Diamanti-Kandarakis E. Polycystic ovary syndrome: definitions, phenotypes and diagnostic approach. Front Horm Res. 2013;40:1–21.

    CAS  PubMed  Google Scholar 

  3. El Hayek S, Bitar L, Hamdar LH, Mirza FG, Daoud G. Polycystic ovarian syndrome: an updated overview. Front Physiol. 2016;7:124.

  4. Navarro VM, Tena-Sempere M. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nat Rev Endocrinol. 2011;8:40–53.

    Article  CAS  PubMed  Google Scholar 

  5. Jayasena CN, Franks S. The management of patients with polycystic ovary syndrome. Nat Rev Endocrinol. 2014;10:624–36.

    Article  PubMed  Google Scholar 

  6. Ramezanali F, Ashrafi M, Hemat M, Arabipoor A, Jalali S, Moini A. Assisted reproductive outcomes in women with different polycystic ovary syndrome phenotypes: the predictive value of anti-Müllerian hormone. Reprod BioMed Online. 2016;32:503–12.

    Article  CAS  PubMed  Google Scholar 

  7. Dewailly D, Robin G, Peigne M, Decanter C, Pigny P, Catteau-Jonard S. Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary. Hum Reprod Update. 2016;22:709–24.

    Article  CAS  PubMed  Google Scholar 

  8. Lv Y, Zhao SG, Lu G, Leung CK, Xiong ZQ, Su XW, et al. Identification of reference genes for qRT-PCR in granulosa cells of healthy women and polycystic ovarian syndrome patients. Sci Rep. 2017;7:6961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li R, Albertini DF. The road to maturation: somatic cell interaction and self-organization of the mammalian oocyte. Nat Rev Mol Cell Biol. 2013;14:141–52.

    Article  CAS  PubMed  Google Scholar 

  10. 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;100:10972–6.

  11. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–27.

    Article  CAS  PubMed  Google Scholar 

  12. Pintado CO, Pinto FM, Pennefather JN, Hidalgo A, Baamonde A, Sanchez T, et al. A role for tachykinins in female mouse and rat reproductive function. Biol Reprod. 2003;69:940–6.

    Article  CAS  PubMed  Google Scholar 

  13. Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, 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;41:354–8.

    Article  CAS  PubMed  Google Scholar 

  14. Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–27.

    Article  PubMed  Google Scholar 

  15. 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;151:3479–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hu G, Lin C, He M, Wong AO. Neurokinin B and reproductive functions: “KNDy neuron” model in mammals and the emerging story in fish. Gen Comp Endocrinol. 2014;208:94–108.

    Article  CAS  PubMed  Google Scholar 

  17. Clarke H, Dhillo WS, Jayasena CN. Comprehensive review on kisspeptin and its role in reproductive disorders. Endocrinol Metab. 2015;30:124–41.

    Article  CAS  Google Scholar 

  18. Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Interactions between neurokinin B and kisspeptin in mediating estrogen feedback in healthy women. J Clin Endocrinol Metab. 2016;101:4628–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Candenas L, Lecci A, Pinto FM, Patak E, Maggi CA, Pennefather JN. Tachykinins and tachykinin receptors: effects in the genitourinary tract. Life Sci. 2005;76:835–62.

    Article  CAS  PubMed  Google Scholar 

  20. Page NM. Neurokinin B and pre-eclampsia: a decade of discovery. Reprod Biol Endocrinol. 2010;8:4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lasaga M, Debeljuk L. Tachykinins and the hypothalamo-pituitary-gonadal axis: an update. Peptides. 2011;32:1972–8.

    Article  CAS  PubMed  Google Scholar 

  22. Satake H, Kawada T. Overview of the primary structure, tissue distribution, and functions of tachykinins and their receptors. Curr Drug Targets. 2006;7:963–74.

    Article  CAS  PubMed  Google Scholar 

  23. Gaytán F, Gaytán M, Castellano JM, Romero M, Roa J, Aparicio B, et al. 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. Am J Physiol Endocrinol Metab. 2009;296:E520–31.

    Article  CAS  PubMed  Google Scholar 

  24. Cejudo Roman A, Pinto FM, Dorta I, Almeida TA, Hernández M, Illanes M, et al. Analysis of the expression of neurokinin B, kisspeptin and their cognate receptors, NK3R and KISS1R in the human female genital tract. Fertil Steril. 2012;97:1213–9.

    Article  CAS  PubMed  Google Scholar 

  25. García-Ortega J, Pinto FM, Fernández-Sánchez M, Prados N, Cejudo-Román A, Almeida TA, et al. Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells. Hum Reprod. 2014;29:2736–46.

    Article  CAS  PubMed  Google Scholar 

  26. Qi X, Salem M, Zhou W, Sato-Shimizu M, Ye G, Smitz J, et al. Neurokinin B exerts direct effects on the ovary to stimulate estradiol production. Endocrinology. 2016;157:3355–65.

    Article  CAS  PubMed  Google Scholar 

  27. Gaytan F, Garcia-Galiano D, Dorfman MD, Manfredi-Lozano M, Castellano JM, Dissen GA, et al. Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. Endocrinology. 2014;155:3088–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bhattacharya M, Babwah AV. Kisspeptin: beyond the brain. Endocrinology. 2015;156:1218–27.

    Article  CAS  PubMed  Google Scholar 

  29. León S, Barroso A, Vázquez MJ, García-Galiano D, Manfredi-Lozano M, Ruiz-Pino F, et al. Direct actions of kisspeptins on GnRH neurons permit attainment of fertility but are insufficient to fully preserve gonadotropic axis activity. Sci Rep. 2016;6:19206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jayasena CN, Abbara A, Comninos AN, Nijher GM, Christopoulos G, Narayanaswamy S, et al. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. J Clin Invest. 2014;124:3667–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Calder M, Chan YM, Raj R, Pampillo M, Elbert A, Noonan M, et al. Implantation failure in female Kiss1-/- mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor. Endocrinology. 2014;155:3065–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fernandois D, Na E, Cuevas F, Cruz G, Lara HE, Paredes AH. Kisspeptin is involved in ovarian follicular development during aging in rats. J Endocrinol. 2016;228:161–70.

    Article  CAS  PubMed  Google Scholar 

  33. Skorupskaite K, George JT, Veldhuis JD, Anderson RA. Neurokinin B regulates gonadotropin secretion, ovarian follicle growth, and the timing of ovulation in healthy women. J Clin Endocrinol Metab. 2018;103:95–104.

    Article  PubMed  Google Scholar 

  34. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25.

    Google Scholar 

  35. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41–7.

    Article  Google Scholar 

  36. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:1–11.

    Article  Google Scholar 

  37. Castellano JM, Navarro VM, Fernández-Fernández R, Nogueiras R, Tovar S, Roa J, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005;146:3917–25.

    Article  CAS  PubMed  Google Scholar 

  38. Dudek M, Ziarniak K, Sliwowska JH. Kisspeptin and metabolism: the brain and beyond. Front Endocrinol. 2018;9:145.

    Article  Google Scholar 

  39. Sánchez-Garrido MA, Ruiz-Pino F, Manfredi-Lozano M, Leon S, Garcia-Galiano D, Castaño JP, et al. Obesity-induced hypogonadism in the male: premature reproductive neuroendocrine senescence and contribution of Kiss1-mediated mechanisms. Endocrinology. 2014;155:1067–79.

    Article  CAS  PubMed  Google Scholar 

  40. Sánchez-Garrido MA, Ruiz-Pino F, Manfredi-Lozano M, Leon S, Heras V, Castellano JM, et al. Metabolic and gonadotropic impact of sequential obesogenic insults in the female: influence of the loss of ovarian secretion. Endocrinology. 2015;156:2984–98.

    Article  CAS  PubMed  Google Scholar 

  41. Xiao Y, Ni Y, Huang Y, Wu J, Grossmann R, Zhao R. Effects of kisspeptin-10 on progesterone secretion in cultured chicken ovarian granulosa cells from preovulatory (F1-F3) follicles. Peptides. 2011;32:2091–7.

    Article  CAS  PubMed  Google Scholar 

  42. Laoharatchatathanin T, Terashima R, Yonezawa T, Kurusu S, Kawaminami M. Augmentation of metastin/kisspeptin mRNA expression by the proestrous luteinizing hormone surge in granulosa cells of rats: implications for luteinization. Biol Reprod. 2015;93:15.

    Article  CAS  PubMed  Google Scholar 

  43. Castellano JM, Gaytan M, Roa J, Vigo E, Navarro VM, Bellido C, et al. Expression of KiSS-1 in rat ovary: putative local regulator of ovulation? Endocrinology. 2006;147:4852–62.

    Article  CAS  PubMed  Google Scholar 

  44. Cielesh ME, McGrath BM, Scott CJ, Norman ST, Stephen CP. The localization of kisspeptin and kisspeptin receptor in the canine ovary during different stages of the reproductive cycle. Reprod Domest Anim. 2017;52:24–8.

    Article  CAS  PubMed  Google Scholar 

  45. George JT, Kakkar R, Marshall J, Scott ML, Finkelman RD, Ho TW, et al. Neurokinin B receptor antagonism in women with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2016;101:4313–21.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by a grant from the Ministerio de Economía y Competitividad (RTC-2014-1431-1), Spain, with joint financing by FEDER funds from the European Union.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Luz Candenas.

Ethics declarations

Approval for this work was obtained from the institutional Ethics Committees of CSIC and Hospital Virgen Macarena (Sevilla, Spain) and all patients gave informed written consent.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Table S1

(DOCX 28 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blasco, V., Pinto, F.M., Fernández-Atucha, A. et al. Altered expression of the kisspeptin/KISS1R and neurokinin B/NK3R systems in mural granulosa and cumulus cells of patients with polycystic ovarian syndrome. J Assist Reprod Genet 36, 113–120 (2019). https://doi.org/10.1007/s10815-018-1338-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-018-1338-7

Keywords

Navigation