Journal of Endocrinological Investigation

, Volume 30, Issue 11, pp 948–956 | Cite as

Effects of ghrelin administration on endocrine and metabolic parameters in obese women with polycystic ovary syndrome

  • A. Fusco
  • A. Bianchi
  • A. Mancini
  • D. Milardi
  • A. Giampietro
  • V. Cimino
  • T. Porcelli
  • D. Romualdi
  • M. Guido
  • A. Lanzone
  • A. Pontecorvi
  • L. De MarinisEmail author
Original Articles


Introduction: The novel peptide ghrelin displays multiple endocrine and non-endocrine actions. Its strong GH-releasing activity in humans has long been recognized. However, in obesity, ghrelin administration induces a blunted GH secretion, enhances glucose and reduces insulin levels. The effects of ghrelin administration have not been investigated in polycystic ovary syndrome (PCOS), which can be associated with obesity, hyperinsulinism, and GH hyposecretion. Leptin is a mediator for energy balance opposed to ghrelin; both of them are supposed to act as regulators of reproductive functions. Aim of the study: Evaluate the endocrine and metabolic response to ghrelin administration in PCOS obese patients compared to body mass index (BMI)-matched and normal weight women. Materials and methods: Nine obese PCOS patients (BMI: 35.4±1.2 kg/m2) (OB PCOS), 6 obese controls (BMI: 38.4±1.1 kg/m2) (Ob), and 6 normal-weight women (BMI: 23±0.6 kg/m2) (NW) were enrolled in the study. In all patients we performed: 1) basal hormonal evaluation including FSH, LH, estradiol, testosterone, androstenedione, DHEAS, SHBG, 17-hydroxyprogesterone (17OHP), IGF-I, free T3 (FT3), free T4 (FT4) and ghrelin levels; 2) metabolic evaluation as follows: concentration of non-esterified fatty acid (NEFA) and oral glucose tolerance test (OGTT) (75 g); homeostasis model assessment (HOMA); glucose and insulin response to ghrelin administration (1 µg/kg); 3) measurement of GH, PRL, TSH, and leptin levels after infusion of ghrelin. Results: Administration of ghrelin increased glucose and reduced insulin levels in both Ob and OB PCOS. Moreover, ghrelin enhanced GH and PRL levels in all groups but it did not modify TSH and leptin levels. GH peak and area under the curve (AUC) in OB PCOS and Ob were lower than controls (p<0.05). Similar PRL peak and AUC values were observed in all groups. Conclusions: In both obese and PCOS obese patients, leptin levels are not influenced by ghrelin administration. Moreover, the GH response after ghrelin administration is blunted. However, ghrelin exerts glucose-enhancing and insulin-lowering effects, the latter absent in NW.


Ghrelin polycystic ovary syndrome obesity leptin GH 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hosoda H, Kojima M, Kangawa K. Biological, physiological and pharmacological aspects of ghrelin. J Pharmacol Sci 2006, 100: 398–410.PubMedCrossRefGoogle Scholar
  2. 2.
    Wren AM, Small CJ, Ward HL, et al The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000, 141: 4325–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Schmid DA, Held K, Ising M, Uhr M, Weikel JC, Steiger A. Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls. Neuropsychopharmacology 2005, 30: 1187–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Takaya K, Ariyasu H, Kanamoto N, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000, 85: 4908–11.PubMedCrossRefGoogle Scholar
  5. 5.
    Tschöp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001, 50: 707–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Tassone F, Broglio F, Destefanis S, et al. Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity. J Clin Endocrinol Metab 2003, 88: 5478–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Lee EJ, Lee BS, Lee HC, Park KH, Song CH, Huh KB. Growth hormone response to L-dopa and pyridostigmine in women with polycystic ovarian syndrome. Fertil Steril 1993, 60: 53–7.PubMedGoogle Scholar
  8. 8.
    Piaditis GP, Kounadi TG, Rangou DB, et al. Dysfunction of the growth hormone/insulin-like growth factor 1 axis in women with polycystic ovarian syndrome. Clin Endocrinol (Oxf) 1995, 42: 635–40.CrossRefGoogle Scholar
  9. 9.
    Morales AJ, Laughlin GA, Bützow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic and luteinizing hormone axes in non-obese and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 1996, 81: 2854–64.PubMedGoogle Scholar
  10. 10.
    Lanzone A, Villa P, Fulghesu AM, Pavone V, Caruso A, Mancuso S. The growth hormone response to growth-hormone-releasing hormone is blunted in polycystic ovary syndrome: relationship with obesity and iperinsulinism. Hum Reprod 1995, 10: 1653–7.PubMedGoogle Scholar
  11. 11.
    Wu XK, Sallinen K, Zhou SY, Su YH, Pöllänen P, Erkkola R. Androgen excess contributes to altered growth hormone/insulin-like growth factor-1 axis in nonobese women with polycystic ovary syndrome. Fertil Steril 2000, 73: 730–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Tena-Sempere M. Exploring the role of ghrelin as novel regulator of gonadal function. Growth Horm IGF Res 2005, 15: 83–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Mantzoros CS, Dunaif A, Flier JS. Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 1997, 82: 1687–91.PubMedGoogle Scholar
  14. 14.
    Rouru J, Anttila L, Koskinen P, et al. Serum leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997, 82: 1697–700.PubMedCrossRefGoogle Scholar
  15. 15.
    Carmina E, Orio F, Palomba S, et al. Evidence for altered adipocyte function in polycystic ovary syndrome. Eur J Endocrinol 2005, 152: 389–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Guido M, Romualdi D, Giuliani M, et al. Effect of metformin on the growth hormone response to growth hormone-releasing hormone in obese women with polycystic ovary syndrome. Fertil Steril 2005, 84: 1470–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Pagotto U, Gambineri A, Vicennati V, Heiman ML, Tschöp M, Pasquali R. Plasma ghrelin, obesity and the polycystic ovary syndrome: correlation with insulin resistence and androgen levels. J Clin Endocrinol Metab 2002, 87: 5625–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Panidis D, Farmakiotis D, Koliakos G, et al. Comparative study of plasma ghrelin levels in women with polycystic ovary syndrome, in hyperandrogenic women and in normal controls. Human Reprod 2005, 20: 2127–32.CrossRefGoogle Scholar
  19. 19.
    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: 4607–10.PubMedCrossRefGoogle Scholar
  20. 20.
    Wasko R, Komarowska H, Warenik-Szymankiewicz A, Sowinski J. Elevated ghrelin plasma levels in patients with polycystic ovary syndrome. Horm Metab Res 2004, 36: 170–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Orio F Jr, Lucidi P, Palomba S, et al. Circulating ghrelin concentrations in the polycystic ovary sindrome. J Clin Endocrinol Metab 2003, 88: 942–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Glintborg D, Andersen M, Hagen C, et al. Evaluation of metabolic risk markers in polycystic ovary sindrome (PCOS). Adiponectin, ghrelin, leptin and body composition in hirsute PCOS patients and controls. Eur J Endocrinol 2006, 155: 337–45.PubMedCrossRefGoogle Scholar
  23. 23.
    Gambineri A, Pagotto U, Tschöp M, et al. Anti-androgen treatment increases circulating ghrelin levels in obese polycystic ovary syndrome. J Endocrinol Invest 2003, 26: 629–34.PubMedCrossRefGoogle Scholar
  24. 24.
    Alvarez-Castro P, Isidro ML, Garcia-Buela J, et al. Marked GH secretion after ghrelin alone or combined with GH-releasing hormone (GHRH) in obese patients. Clin Endocrinol (Oxf) 2004, 61: 250–5.CrossRefGoogle Scholar
  25. 25.
    Micic D, Kendereski A, Popovic V, et al. Growth hormone response to GHRH, GHRP-6 and GHRH+GHRP-6 in patients with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1996, 45: 385–90.CrossRefGoogle Scholar
  26. 26.
    De Marinis L, Mancini A, Zuppi P, et al. Influence of pyridostigmine on ghrowth hormone response to growth hormone (GH)-releasing hormone pre- and postprandially in normal and obese subjects. J Clin Endocrinol Metab 1992, 74: 1253–7.PubMedGoogle Scholar
  27. 27.
    Diamond MP, Hallarman L, Starick-Zych K, et al. Suppression of counterregulatory hormone response to hypoglycemia by insulin per se. J Clin Endocrinol Metab 1991, 72: 1388–90.PubMedCrossRefGoogle Scholar
  28. 28.
    De Marinis L, Mancini A, Valle D, et al. Influence of chronic Naltrexone treatment on growth hormone and insulin secretion in obese subjects. Int J Obes Rel Metab Disord 1997, 21: 1076–81.CrossRefGoogle Scholar
  29. 29.
    Casanueva FF, Villanueva L, Dieguez C, et al. Free fatty acids block growth hormone (GH) releasing hormone-stimulated GH secretion in man directly at the pituitary. J Clin Endocrinol Metab 1987, 65: 634–42.PubMedCrossRefGoogle Scholar
  30. 30.
    Cordido F, Peino R, Peñalva A, Alvarez CV, Casanueva FF, Dieguez C. Impaired GH secretion in obese subjects is partially reversed by Acipimox-mediated plasma free fatty acid depression. J Clin Endocrinol Metab 1996, 81: 914–9.PubMedGoogle Scholar
  31. 31.
    Maccario M, Procopio M, Grottoli S, et al. Effects of acipimox, an antilipolytic drug, on the growth hormone response to GH-reelasing hormone alone or combined with arginine in obesity. Metabolism 1996, 45: 342–6.PubMedCrossRefGoogle Scholar
  32. 32.
    De Marinis L, Bianchi A, Mancini A, et al. Growth hormone secretion and leptin in morbid obesity before and after biliopancreatic diversion: relationships with insulin and body composition. J Clin Endocrinol Metab 2004, 89: 174–80.PubMedCrossRefGoogle Scholar
  33. 33.
    Luque RM, Kineman RD. Impact of obesity on the growth hormone axis: evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function. Endocrinology 2006, 147: 2754–63.PubMedCrossRefGoogle Scholar
  34. 34.
    Orio F Jr, Palomba S, Colao A, et al. GH release after GHRH plus arginine administration in obese and overweight women with polycystic ovary syndrome. J Endocrinol Invest 2003, 26: 117–22.PubMedCrossRefGoogle Scholar
  35. 35.
    de Boer JA, Lambalk CB, Hendriks HH, van Aken C, van der Veen EA, Schoemaker J. Growth hormone secretion is impaired but not related to insulin sensitivity in non-obese patients with polycystic ovary syndrome. Human Reprod 2004, 19: 504–9.CrossRefGoogle Scholar
  36. 36.
    Möhlig M, Spranger J, Otto B, Ristow M, Tschöp M, Pfeiffer AF. Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans. J Endocrinol Invest 2002, 25: RC36–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Saad MF, Bernaba B, Hwu CM, et al. Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab 2002, 87: 3997–4000.PubMedCrossRefGoogle Scholar
  38. 38.
    Purnell JQ, Weigle DS, Breen P, Cummings DE. Ghrelin levels correlate with insulin levels, insulin resistance and high-density lipoprotein cholesterol, but not with gender, menopausal status or cortisol levels in humans. J Clin Endocrinol Metab 2003, 88: 5747–52.PubMedCrossRefGoogle Scholar
  39. 39.
    Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycaemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 2001, 86: 5083–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Egido EM, Rodriguez-Gallardo J, Silvestre RA, Marco J. Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion. Eur J Endocrinol 2002, 146: 241–4.PubMedCrossRefGoogle Scholar
  41. 41.
    Rubinfeld H, Hadani M, Taylor JE, et al. Novel ghrelin analogs with improved affinity for the GH secretagogue receptor stimulate GH and prolactin release from human pituitary cells. Eur J Endocrinology 2004, 151: 787–95.CrossRefGoogle Scholar
  42. 42.
    Laughlin GA, Morales AJ, Yen SSC. Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab 1997, 82: 1692–6.PubMedGoogle Scholar
  43. 43.
    Remsberg KE, Talbott EO, Zborowski JV, Evans RW, McHugh-Pemu K. Evidence for competing effects of body mass, hyperinsulinemia, insulin resistance, and androgens on leptin levels among lean, overweight and obese women with polycystic ovary syndrome. Fertil Steril 2002, 78: 479–86.PubMedCrossRefGoogle Scholar
  44. 44.
    Brzechffa PR, Jakimiuk AJ, Agarwal SK, Weitsman SR, Buyalos RP, Magoffin DA. Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1996, 81: 4166–9.PubMedGoogle Scholar
  45. 45.
    Pirwany IR, Fleming R, Sattar N, Greer IA, Wallace AM. Circulating leptin concentrations and ovarian function in polycystic ovary syndrome. Eur J Endocrinol 2001, 145: 289–94.PubMedCrossRefGoogle Scholar
  46. 46.
    Kolaczynski JW, Nyce MR, Considine RV, et al. Acute and chronic effect of insulin on leptin production in humans. Studies in vivo and in vitro. Diabetes 1996, 45: 699–701.PubMedCrossRefGoogle Scholar
  47. 47.
    Wabitsch M, Jensen PB, Blum WF, et al. Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes 1996, 45: 1435–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Ciaraldi TP, el-Roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SS. Cellular mechanisms of insulin resistance in polcycystic ovarian syndrome. J Clin Endocrinol Metab 1992, 75: 577–83.PubMedGoogle Scholar
  49. 49.
    Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Amer J Physiol 1993, 264: E197–202.PubMedGoogle Scholar
  50. 50.
    Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin-resistance in the polycystic ovary syndrome. J Clin Invest 1995, 96: 801–10.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Ciaraldi TP, Morales AJ, Hickman MG, Odom-Ford R, Olefsky JM, Yen SS. Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity. J Clin Endocrinol Metab 1997, 82: 1421–5.PubMedGoogle Scholar
  52. 52.
    Björntorp P. The android woman — a risky condition. J Intern Med 1996, 239: 105–10.PubMedCrossRefGoogle Scholar
  53. 53.
    Roemmich JN, Clark PA, Berr SS, et al. Gender differences in leptin levels during puberty are related to the subcutaneous fat depot and sex steroid. Am J Physiol 1998, 275: E543–51.PubMedGoogle Scholar
  54. 54.
    Demerath EV, Towne B, Wisemandle W, Blangero J, Chumlea WC, Siervogel RM. Serum leptin concentration, body composition, and gonadal hormones during puberty. Int J Obes Relat Metab Disord 1999, 23: 678–85.PubMedCrossRefGoogle Scholar
  55. 55.
    Jockenhövel F, Blum W, Vogel E, et al Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. J Clin Endocrinol Metab 1997, 82: 2510–3.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2007

Authors and Affiliations

  • A. Fusco
    • 1
  • A. Bianchi
    • 1
  • A. Mancini
    • 1
  • D. Milardi
    • 2
  • A. Giampietro
    • 2
  • V. Cimino
    • 1
  • T. Porcelli
    • 1
  • D. Romualdi
    • 3
  • M. Guido
    • 3
  • A. Lanzone
    • 3
  • A. Pontecorvi
    • 1
  • L. De Marinis
    • 1
    Email author
  1. 1.Section of Endocrinology, Department of Internal MedicineCatholic University School of MedicineRomeItaly
  2. 2.International Scientific Institute “Paolo VI”Catholic University School of MedicineRomeItaly
  3. 3.Department of GynecologyCatholic University School of MedicineRomeItaly

Personalised recommendations