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Ghrelin

New Insights into Female Reproductive System–Associated Disorders and Pregnancy

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Abstract

Ghrelin is considered the endogenous ligand of growth hormone secretagogue receptor type 1a, and its modulatory actions have been demonstrated in a large array of endocrine and nonendocrine functions. According to recent studies, ghrelin seems to act at different levels of the reproductive system, exerting predominantly inhibitory effects on mammalian reproduction. It has been shown to influence the reproductive system by regulating hormone secretion from the brain and by acting directly on the gonads to affect tissue development and steroidogenesis. Thus, the endocrine network, which integrates energy balance and fertility, might involve ghrelin. Furthermore, ghrelin levels and actions have been assessed in various female reproductive system disorders. The findings could lead to a better understanding of the pathogenesis of these disorders and, possibly, to more beneficial therapeutic strategies.

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References

  1. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660.

    Article  CAS  PubMed  Google Scholar 

  2. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–977.

    Article  CAS  PubMed  Google Scholar 

  3. Locatelli V, Torsello A. Growth hormone secretagogues: focus on the growth hormone releasing peptides. Pharmacol Res. 1997; 36(6):415–423.

    Article  CAS  PubMed  Google Scholar 

  4. Angelidis G, Valotassiou V, Georgoulias P. Current and potential roles of ghrelin in clinical practice. J Endocrinol Invest. 2010; 33(11):823–838.

    Article  CAS  PubMed  Google Scholar 

  5. Broglio F, Benso A, Gottero C, et al. Non-acylated ghrelin does not possess the pituitaric and pancreatic endocrine activity of acylated ghrelin in humans. J Endocrinol Invest. 2003;26(3): 192–196.

    Article  CAS  PubMed  Google Scholar 

  6. García MC, López M, Alvarez CV, Casanueva F, Tena-Sempere M, Diéguez C. Role of ghrelin in reproduction. Reproduction. 2007;133(3):531–540.

    Article  PubMed  CAS  Google Scholar 

  7. Kluge M, Schussler P, Uhr M, Yassouridis A, Steiger A. Ghrelin suppresses secretion of luteinizing hormone in humans. J Clin Endocrinol Metab. 2007;92(8):3202–3205.

    Article  CAS  PubMed  Google Scholar 

  8. Furuta M, Funabashi T, Kimura F. Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats. Biochem Biophys Res Commun. 2001;288(4):780–785.

    Article  CAS  PubMed  Google Scholar 

  9. Fernández-Fernández R, Tena-Sempere M, Navarro VM, et al. Effects of ghrelin upon gonadotropin-releasing hormone and gonadotropin secretion in adult female rats: in vivo and in vitro studies. Neuroendocrinology. 2005;82(5–6):245–255.

    Article  PubMed  CAS  Google Scholar 

  10. Ogata R, Matsuzaki T, Iwasa T, et al. Hypothalamic ghrelin suppresses pulsatile secretion of luteinizing hormone via beta-endorphin in ovariectomized rats. Neuroendocrinology. 2009; 90(4):364–370.

    Article  CAS  PubMed  Google Scholar 

  11. Martini AC, Fernandez-Fernandez R, Tovar S, et al. Comparative analysis of the effects of ghrelin and unacylated ghrelin on luteinizing hormone secretion in male rats. Endocrinology. 2006; 147(5):2374–2382.

    Article  CAS  PubMed  Google Scholar 

  12. Sokołowska-Mikołajczyk M, Socha M, Szczerbik P, Epler P. The effects of ghrelin on the in vitro spontaneous and sGnRH-A stimulated luteinizing hormone (LH) release from the pituitary cells of common carp (Cyprinus carpio L.). Comp Biochem Physiol A Mol Integr Physiol. 2009;153(4):386–390.

    Article  PubMed  CAS  Google Scholar 

  13. Lanfranco F, Bonelli L, Baldi M, Me E, Broglio F, Ghigo E. Acylated ghrelin inhibits spontaneous luteinizing hormone pulsatility and responsiveness to naloxone but not that to gonadotrophin-releasing hormone in young men: evidence for a central inhibitory action of ghrelin on the gonadal axis. J Clin Endocrinol Metab. 2008;93(9):3633–3639.

    Article  CAS  PubMed  Google Scholar 

  14. Kluge M, Uhr M, Bleninger P, Yassouridis A, Steiger A. Ghrelin suppresses secretion of FSH in males. Clin Endocrinol (Oxf). 2009;70(6):920–923.

    Article  CAS  Google Scholar 

  15. Messini CI, Dafopoulos K, Chalvatzas N, Georgoulias P, Messinis IE. Effect of ghrelin on gonadotrophin secretion in women during the menstrual cycle. Hum Reprod. 2009;24(4): 976–981.

    Article  CAS  PubMed  Google Scholar 

  16. Dafopoulos K, Sourlas D, Kallitsaris A, Pournaras S, Messinis IE. Blood ghrelin, resistin, and adiponectin concentrations during the normal menstrual cycle. Fertil Steril. 2009;92(4):1389–1394.

    Article  CAS  PubMed  Google Scholar 

  17. Dafopoulos K, Chalvatzas N, Kosmas G, Kallitsaris A, Pournaras S, Messinis IE. The effect of estrogens on plasma ghrelin concentrations in women. J Endocrinol Invest. 2010;33(2):109–112.

    Article  CAS  PubMed  Google Scholar 

  18. Du C, Li H, Cao G, Xilingaowa, Wang C, Li C. Expression of the orexigenic peptide ghrelin and the type 1a growth hormone secre-tagogue receptor in sheep oocytes and pre-implantation embryos produced in vitro. Reprod Domest Anim. 2010;45(1):92–98.

    Article  CAS  PubMed  Google Scholar 

  19. Sirotkin AV, Grossmann R, María-Peon MT, Roa J, Tena-Sempere M, Klein S. Novel expression and functional role of ghrelin in chicken ovary. Mol Cell Endocrinol. 2006;257–258:15–25.

    Article  CAS  PubMed  Google Scholar 

  20. Sirotkin AV, Grossmann R. Effects of ghrelin and its analogues on chicken ovarian granulosa cells. Domest Anim Endocrinol. 2008;34(2):125–134.

    Article  CAS  PubMed  Google Scholar 

  21. Sirotkin AV, Chrenek P, Darlak K, Valenzuela F, Kuklová Z. Some endocrine traits of transgenic rabbits. II. Changes in hormone secretion and response of isolated ovarian tissue to FSH and ghrelin. Physiol Res. 2008;57(5):745–751.

    CAS  PubMed  Google Scholar 

  22. Sirotkin AV, Rafay J, Kotwica J, Darlak K, Valenzuela F. Role of ghrelin in regulating rabbit ovarian function and the response to LH and IGF-I. Domest Anim Endocrinol. 2009;36(3):162–172.

    Article  CAS  PubMed  Google Scholar 

  23. Sirotkin AV, Rafay J, Kotwica J. Leptin controls rabbit ovarian function in vivo and in vitro: possible interrelationships with ghrelin. Theriogenology. 2009;72(6):765–772.

    Article  CAS  PubMed  Google Scholar 

  24. Chrenek P, Grossmann R, Sirotkin AV. The cAMP analogue, dbcAMP affects release of steroid hormones by cultured rabbit ovarian cells and their response to FSH, IGF-I and ghrelin. Eur J Pharmacol. 2010;640(1–3):202–205.

    Article  CAS  PubMed  Google Scholar 

  25. Sirotkin AV, Meszarosová M. Comparison of effects of leptin and ghrelin on porcine ovarian granulosa cells. Domest Anim Endocrinol. 2010;39(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  26. Viani I, Vottero A, Tassi F, et al. Ghrelin inhibits steroid biosynthesis by cultured granulose-lutein cells. J Clin Endocrinol Metab. 2008;93(4):1476–1481.

    Article  CAS  PubMed  Google Scholar 

  27. Mircea CN, Lujan ME, Pierson RA. Metabolic fuel and clinical implications for female reproduction. J Obstet Gynaecol Can. 2007;29(11):887–902.

    Article  PubMed  Google Scholar 

  28. Abou Heif HM, Deif MM, Abdel Aziz HK. Effect of food restriction on ghrelin in adult male rats and its relation to male reproductive hormones. Andrologia. 2010;42(2):97–105.

    Article  CAS  PubMed  Google Scholar 

  29. Vulliémoz NR, Xiao E, Xia-Zhang L, Germond M, Rivier J, Ferin M. Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab. 2004;89(11):5718–5723.

    Article  PubMed  CAS  Google Scholar 

  30. Aghajanova L, Rumman A, Altmäe S, Wånggren K, Stavreus-Evers A. Diminished endometrial expression of ghrelin and ghrelin receptor contributes to infertility. Reprod Sci. 2010;17(9): 823–832.

    Article  CAS  PubMed  Google Scholar 

  31. Martin JR, Lieber SB, McGrath J, Shanabrough M, Horvath TL, Taylor HS. Maternal ghrelin deficiency compromises reproduction in female progeny through altered uterine developmental programming. Endocrinology. 2011;152(5):2060–2066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Castellano JM, Bentsen AH, Mikkelsen JD, Tena-Sempere M. Kisspeptins: bridging energy homeostasis and reproduction. Brain Res. 2010;1364:129–138.

    Article  CAS  PubMed  Google Scholar 

  33. Tena-Sempere M. KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology. 2006; 83(5–6):275–281.

    Article  CAS  PubMed  Google Scholar 

  34. Budak E, Fernández Sánchez M, Bellver J, Cerveró A, Simón C, Pellicer A. Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system. Fertil Steril. 2006;85(6):1563–1581.

    Article  CAS  PubMed  Google Scholar 

  35. Rak-Mardyła A, Gregoraszczuk E. Effect of ghrelin on proliferation, apoptosis and secretion of progesterone and hCG in the placental JEG-3 cell line. Reprod Biol. 2010;10(2):159–165.

    Article  PubMed  Google Scholar 

  36. Tanaka K, Minoura H, Isobe T, et al. Ghrelin is involved in the decidualization of human endometrial stromal cells. J Clin Endo-crinol Metab. 2003;88(5):2335–2340.

    Article  CAS  PubMed  Google Scholar 

  37. Tawadros N, Salamonsen LA, Dimitriadis E, Chen C. Facilitation of decidualization by locally produced ghrelin in the human endometrium. Mol Hum Reprod. 2007;13(7):483–489.

    Article  CAS  PubMed  Google Scholar 

  38. O’Brien M, Earley P, Morrison JJ, Smith TJ. Ghrelin in the human myometrium. Reprod Biol Endocrinol. 2010;8:55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Fuglsang J, Skjaerbaek C, Espelund U, et al. Ghrelin and its relationship to growth hormones during normal pregnancy. Clin Endocrinol (Oxf). 2005;62(5):554–559.

    Article  CAS  Google Scholar 

  40. Palik E, Baranyi E, Melczer Z, et al. Elevated serum acylated (biologically active) ghrelin and resistin levels associate with pregnancy-induced weight gain and insulin resistance. Diabetes Res Clin Pract. 2007;76(3):351–357.

    Article  CAS  PubMed  Google Scholar 

  41. Riedl M, Maier C, Handisurya A, Luger A, Kautzky-Willer A. Insulin resistance has no impact on ghrelin suppression in pregnancy. J Intern Med. 2007;262(4):458–465.

    Article  CAS  PubMed  Google Scholar 

  42. Makino Y, Hosoda H, Shibata K, et al. Alteration of plasma ghrelin levels associated with the blood pressure in pregnancy. Hypertension. 2002;39(3):781–784.

    Article  CAS  PubMed  Google Scholar 

  43. Tham E, Liu J, Innis S, et al. Acylated ghrelin concentrations are markedly decreased during pregnancy in mothers with and without gestational diabetes: relationship with cholinesterase. Am J Physiol Endocrinol Metab. 2009;296(5):1093–1100.

    Article  CAS  Google Scholar 

  44. Gibson W, Liu J, Gaylinn B, et al. Effects of glucose and insulin on acyl ghrelin and desacyl ghrelin, leptin, and adiponectin in pregnant women with diabetes. Metabolism. 2010;59(6): 841–847.

    Article  CAS  PubMed  Google Scholar 

  45. Telejko B, Kuzmicki M, Zonenberg A, et al. Ghrelin in gestational diabetes: serum level and mRNA expression in fat and placental tissue. Exp Clin Endocrinol Diabetes. 2010;118(2): 87–92.

    Article  CAS  PubMed  Google Scholar 

  46. Poston L. Leptin and preeclampsia. Semin Reprod Med. 2002; 20(2):131–138.

    Article  CAS  PubMed  Google Scholar 

  47. Aydin S, Guzel SP, Kumru S, et al. Serum leptin and ghrelin concentrations of maternal serum, arterial and venous cord blood in healthy and preeclamptic pregnant women. J Physiol Biochem. 2008;64(1):51–59.

    Article  CAS  PubMed  Google Scholar 

  48. Kawamura K, Sato N, Fukuda J, et al. Ghrelin inhibits the development of mousepreimplantation embryos in vitro. Endocrinology. 2003;144(6):2623–2633.

    Article  CAS  PubMed  Google Scholar 

  49. Fernandez-Fernandez R, Navarro VM, Barreiro ML, et al. Effects of chronic hyperghrelinemia on puberty onset and pregnancy outcome in the rat. Endocrinology. 2005;146(7):3018–3025.

    Article  CAS  PubMed  Google Scholar 

  50. Hayashida T, Nakahara K, Mondal MS, et al. Ghrelin in neonatal rats: distribution in stomach and its possible role. J Endocrinol. 2002;173(2):239–245.

    Article  CAS  PubMed  Google Scholar 

  51. Nakahara K, Nakagawa M, Baba Y, et al. Maternal ghrelin plays an important role in rat fetal development during pregnancy. Endocrinology. 2006;147(3):1333–1342.

    Article  CAS  PubMed  Google Scholar 

  52. Saad A, Abbas OA. Ghrelin as a regulator of gonadal function in adult male offsprings exposed to cigarette smoking in utero. Endocr Regul. 2009;43(4):141–148.

    CAS  PubMed  Google Scholar 

  53. Volante M, Fulcheri E, Allia E, Cerrato M, Pucci A, Papotti M. Ghrelin expression in fetal, infant, and adult human lung. J Histochem Cytochem. 2002;50(8):1013–1021.

    Article  CAS  PubMed  Google Scholar 

  54. Kyriakakou M, Malamitsi-Puchner A, Mastorakos G, et al. The role of IGF-1 and ghrelin in the compensation of intrauterine growth restriction. Reprod Sci. 2009;16(12):1193–1200.

    Article  CAS  PubMed  Google Scholar 

  55. Tena-Sempere M. Exploring the role of ghrelin as novel regulator of gonadal function. Growth Horm IGF Res. 2005;15(2):83–88.

    Article  CAS  PubMed  Google Scholar 

  56. Messini C, Dafopoulos K, Chalvatzas N, Georgoulias P, Messinis IE. Growth hormone and prolactin response to ghrelin during the normal menstrual cycle. Clin Endocrinol (Oxf). 2009;71(3): 383–387.

    Article  CAS  Google Scholar 

  57. Messini CI, Dafopoulos K, Chalvatzas N, Georgoulias P, Anifandis G, Messinis IE. Effect of ghrelin and thyrotropin-releasing hormone on prolactin secretion in normal women. Horm Metab Res. 2010;42(3):204–208.

    Article  CAS  PubMed  Google Scholar 

  58. Messini CI, Dafopoulos K, Chalvatzas N, Georgoulias P, Anifandis G, Messinis IE. Blockage of ghrelin-induced prolactin secretion in women by bromocriptine. Fertil Steril. 2010;94(4): 1478–1481.

    Article  CAS  PubMed  Google Scholar 

  59. Dündar NO, Dündar B, Cesur G, Yilmaz N, Sütçu R, Ozgüner F. Ghrelin and adiponectin levels in colostrum, cord blood and maternal serum. Pediatr Int. 2010;52(4):622–625.

    Article  PubMed  CAS  Google Scholar 

  60. Aydin S. The presence of the peptides apelin, ghrelin and nesfatin-1 in the human breast milk, and the lowering of their levels in patients with gestational diabetes mellitus. Peptides. 2010; 31(12):2236–2240.

    Article  CAS  PubMed  Google Scholar 

  61. Larson-Meyer DE, Ravussin E, Heilbronn L, DeJonge L. Ghrelin and peptide YY in postpartum lactating and nonlactating women. Am J Clin Nutr. 2010;91(2):366–372.

    Article  CAS  PubMed  Google Scholar 

  62. Vrbikova J, Hainer V. Obesity and polycystic ovary syndrome. Obes Facts. 2009;2(1):26–35.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Waśko R, Komarowska H, Warenik-Szymankiewicz A, Sowiński J. Elevated ghrelin plasma levels in patients with polycystic ovary syndrome. Horm Metab Res. 2004;36(3):170–173.

    Article  PubMed  CAS  Google Scholar 

  64. Daghestani MH, Daghestani MH, El-Mazny A. Circulating ghrelin levels and the polycystic ovary syndrome: correlation with the clinical, hormonal and metabolic features. Eur J Obstet Gynecol Reprod Biol. 2011;155(1):65–68.

    Article  CAS  PubMed  Google Scholar 

  65. Schöfl C, Horn R, Schill T, Schlösser HW, Müller MJ, Brabant G. Circulating ghrelin levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(10):4607–4610.

    Article  PubMed  CAS  Google Scholar 

  66. Panidis D, Asteriadis C, Georgopoulos NA, et al. Decreased active, total and altered active to total ghrelin ratio in normal weight women with the more severe form of polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2010;149(2):170–174.

    Article  CAS  PubMed  Google Scholar 

  67. Ozgen IT, Aydin M, Guven A, Aliyazicıoglu Y. Characteristics of polycystic ovarian syndrome and relationship with ghrelin in adolescents. J Pediatr Adolesc Gynecol. 2010;23(5):285–289.

    Article  CAS  PubMed  Google Scholar 

  68. Guido M, Romualdi D, De Marinis L, et al. Administration of exogenous ghrelin in obese patients with polycystic ovary syndrome: effects on plasma levels of growth hormone, glucose, and insulin. Fertil Steril. 2007;88(1):125–130.

    Article  CAS  PubMed  Google Scholar 

  69. Fusco A, Bianchi A, Mancini A, et al. Effects of ghrelin administration on endocrine and metabolic parameters in obese women with polycystic ovary syndrome. J Endocrinol Invest. 2007; 30(11):948–956.

    Article  CAS  PubMed  Google Scholar 

  70. Nishi Y, Yoh J, Hiejima H, Kojima M. Structures and molecular forms of the ghrelin-family peptides. Peptides. 2011;32(11): 2175–2182.

    Article  CAS  PubMed  Google Scholar 

  71. Kaiya H, Kojima M, Hosoda H, et al. Bullfrog ghrelin is modified by n-octanoic acid at its third threonine residue. J Biol Chem. 2001;276(44):40441–40448.

    Article  CAS  PubMed  Google Scholar 

  72. Kaiya H, Kojima M, Hosoda H, et al. Amidated fish ghrelin: purification, cDNA cloning in the Japanese eel and its biological activity. J Endocrinol. 2003;176(3):415–423.

    Article  CAS  PubMed  Google Scholar 

  73. Hiejima H, Nishi Y, Hosoda H, et al. Regional distribution and the dynamics of n-decanoyl ghrelin, another acyl-form of ghrelin, upon fasting in rodents. Regul Pept. 2009;156(1–3):47–56.

    Article  CAS  PubMed  Google Scholar 

  74. Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K. Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem. 2003;278(1):64–70.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Nuclear Medicine, Medical School, University of Thessalia, Mezourlo, 41110 Larissa, Greece

    George Angelidis MD, Varvara Valotassiou MD & Panagiotis Georgoulias MD

  2. Department of Obstetrics and Gynecology, Medical School, University of Thessalia, Larissa, Greece

    Konstantinos Dafopoulos MD, Christina I. Messini MD & Ioannis E. Messinis MD, PhD

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  1. George Angelidis MD
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  2. Konstantinos Dafopoulos MD
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  3. Christina I. Messini MD
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  4. Varvara Valotassiou MD
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  5. Panagiotis Georgoulias MD
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  6. Ioannis E. Messinis MD, PhD
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Correspondence to Panagiotis Georgoulias MD.

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Angelidis, G., Dafopoulos, K., Messini, C.I. et al. Ghrelin. Reprod. Sci. 19, 903–910 (2012). https://doi.org/10.1177/1933719112443880

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