Advertisement

Journal of Endocrinological Investigation

, Volume 28, Issue 1, pp 882–892 | Cite as

Ovarian steroids modulate neuroendocrine dysfunction in polycystic ovary syndrome

  • S. A. R. Doi
  • M. Al-Zaid
  • P. A. Towers
  • C. J. Scott
  • K. A. S. Al-Shoumer
Original Article

Abstract

Objective: Neuroendocrine dysfunction in polycystic ovary syndrome (PCOS) was addressed by studying the steroid hormone changes in women with PCOS with either high or normal LH levels leading to inferences regarding the primacy of elevated LH in the pathophysiology of PCOS. Methods: A cross-sectional study was designed in an academic clinical facility involving 234 women with PCOS. Patients were divided into two groups based on an LH/FSH ratio < or >1 and hormonal and metabolic studies were performed in both groups. Factors were determined by binomial logistic regression that predicted group membership of these women. Results: Higher follicular phase estradiol (E2) and androstenedione (A4) levels as well as greater insulin sensitivity were the only factors that predicted the presence of neuroendocrine dysfunction with elevated A4 being necessary for neuroendocrine dysfunction. Conclusions: It was concluded that uncoupling of hypothalamic E2 inhibition by elevated ovarian A4 associated with E2 related sensitization of pituitary LH leads to neuroendocrine dysfunction in PCOS.

Key-words

Polycystic ovary steroid LH pituitary hypothalamus 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Franks S. Adult polycystic ovary syndrome begins in childhood. Best Pract Res Clin Endocrinol Metab 2002, 16: 263–72.PubMedCrossRefGoogle Scholar
  2. 2.
    Berga SL, Daniels TL. Can polycystic ovary syndrome exist without concomitant hypothalamic dysfunction? Semin Reprod Endocrinol 1997, 15: 169–75.PubMedCrossRefGoogle Scholar
  3. 3.
    Marshall JC, Eagleson CA, McCartney CR. Hypothalamic dysfunction. Mol Cell Endocrinol 2001, 183: 29–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Kazer RR, Liu CH, Yen SS. Dependence of mean levels of circulating luteinizing hormone upon pulsatile amplitude and frequency. J Clin Endocrinol Metab 1987, 65: 796–800.PubMedCrossRefGoogle Scholar
  5. 5.
    Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, Naftolin F. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 1976, 57: 1320–9.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Hayes FJ, Taylor AE, Martin KA, Hall JE. Use of a gonadotropin-releasing hormone antagonist as a physiologic probe in polycystic ovary syndrome: assessment of neuroendocrine and androgen dynamics. J Clin Endocrinol Metab 1998, 83: 2343–9.PubMedGoogle Scholar
  7. 7.
    Gilling-Smith C, Willis DS, Beard RW, Franks S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab 1994, 79: 1158–65.PubMedGoogle Scholar
  8. 8.
    Ibanez L, Hall JE, Potau N, Carrascosa A, Prat N, Taylor AE. Ovarian 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary syndrome is not mediated by luteinizing hormone hypersecretion: evidence from GnRH agonist and human chorionic gonadotropin stimulation testing. J Clin Endocrinol Metab 1996, 81: 4103–7.PubMedGoogle Scholar
  9. 9.
    Levrant SG, Barnes RB, Rosenfield RL. A pilot study of the human chorionic gonadotrophin test for ovarian hyperandrogenism. Hum Reprod 1997, 12: 1416–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Gilling-Smith C, Story H, Rogers V, Franks S. Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1997, 47: 93–9.CrossRefGoogle Scholar
  11. 11.
    Yen SS. The polycystic ovary syndrome. Clin Endocrinol (Oxf) 1980, 12: 177–207.CrossRefGoogle Scholar
  12. 12.
    Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J (Clin Res Ed) 1986, 293: 355–9.CrossRefGoogle Scholar
  13. 13.
    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
  14. 14.
    Jahanfar S, Eden JA. Idiopathic hirsutism or polycystic ovary syndrome? Aust N Z J Obstet Gynaecol 1993, 33: 414–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Carmina E, Lobo RA. Do hyperandrogenic women with normal menses have polycystic ovary syndrome? Fertil Steril 1999, 71: 319–22.PubMedCrossRefGoogle Scholar
  16. 16.
    Carmina E, Lobo RA. Polycystic ovaries in Hirsute women with normal menses. Am J Med 2001, 111: 602–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A 1998, 95: 14956–60.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C. Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist? Metabolism 1997, 46: 902–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961, 21: 1440–7.PubMedCrossRefGoogle Scholar
  20. 20.
    van Hooff MH, van der Meer M, Lambalk CB, Schoemaker J. Variation of luteinizing hormone and androgens in oligomenorrhoea and its implications for the study of polycystic ovary syndrome. Hum Reprod 1999, 14: 1684–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Milsom SR, Sowter MC, Carter MA, Knox BS, Gunn AJ. LH levels in women with polycystic ovarian syndrome: have modern assays made them irrelevant? BJOG 2003, 110: 760–4.PubMedCrossRefGoogle Scholar
  22. 22.
    Manieri C, Pastorino R, Marolda AR, et al. Gonadotropin evaluation in the diagnosis of polycystic ovary syndrome using either a monoclonal or a polyclonal antibody radioimmunoassay. J Endocrinol Invest 1992, 15: 219–22.PubMedCrossRefGoogle Scholar
  23. 23.
    Arroyo A, Laughlin GA, Morales AJ, Yen SS. Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. J Clin Endocrinol Metab 1997, 82: 3728–33.PubMedGoogle Scholar
  24. 24.
    Campbell PJ, Gerich JE. Impact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesity. J Clin Endocrinol Metab 1990, 70: 1114–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Radziuk J. Insulin sensitivity and its measurement: structural commonalities among the methods. J Clin Endocrinol Metab 2000, 85: 4426–33.PubMedGoogle Scholar
  26. 26.
    Mather KJ, Hunt AE, Steinberg HO, et al. Repeatability characteristics of simple indices of insulin resistance: implications for research applications. J Clin Endocrinol Metab 2001, 86: 5457–64.PubMedCrossRefGoogle Scholar
  27. 27.
    Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 1998, 21: 2191–2.PubMedCrossRefGoogle Scholar
  28. 28.
    Quon MJ. Limitations of the fasting glucose to insulin ratio as an index of insulin sensitivity. J Clin Endocrinol Metab 2001, 86: 4615–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril 2000, 73: 150–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Carani C, Qin K, Simoni M, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997, 337: 91–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 1994, 78: 1287–92.PubMedGoogle Scholar
  32. 32.
    Kesner JS, Wilson RC, Kaufman JM, et al. Unexpected responses of the hypothalamic gonadotropin-releasing hormone “pulse generator” to physiological estradiol inputs in the absence of the ovary. Proc Natl Acad Sci U S A 1987, 84: 8745–9.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Patel K, Coffler MS, Dahan MH, Malcom PJ, Deutsch R, Chang RJ. Relationship of GnRH-stimulated LH release to episodic LH secretion and baseline endocrine-metabolic measures in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2004, 60: 67–74.CrossRefGoogle Scholar
  34. 34.
    Eagleson CA, Gingrich MB, Pastor CL, et al. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 2000, 85: 4047–52.PubMedGoogle Scholar
  35. 35.
    De Leo V, Lanzetta D, D’Antona D, la Marca A, Morgante G. Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998, 83: 99–102.PubMedCrossRefGoogle Scholar
  36. 36.
    Sir T. [Do androgens modulate luteinizing hormone secretion in women?]. Rev Med Chil 1997, 125: 710–8.PubMedGoogle Scholar
  37. 37.
    Sir-Petermann T, Rabenbauer B, Wildt L. The effect of flutamide on pulsatile gonadotrophin secretion in hyperandrogenaemic women. Hum Reprod 1993, 8: 1807–12.PubMedGoogle Scholar
  38. 38.
    Dunaif A, Longcope C, Canick J, Badger T, Crowley WF Jr. The effects of the aromatase inhibitor delta 1-testolactone on gonadotropin release and steroid metabolism in polycystic ovarian disease. J Clin Endocrinol Metab 1985, 60: 773–80.PubMedCrossRefGoogle Scholar
  39. 39.
    Dunaif A, Scully RE, Andersen RN, Chapin DS, Crowley WF Jr. The effects of continuous androgen secretion on the hypothalamic-pituitary axis in woman: evidence from a luteinized thecoma of the ovary. J Clin Endocrinol Metab 1984, 59: 389–93.PubMedCrossRefGoogle Scholar
  40. 40.
    Judd HL, Rigg LA, Anderson DC, Yen SS. The effects of ovarian wedge resection on circulating gonadotropin and ovarian steroid levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 1976, 43: 347–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Greenblatt E, Casper RF. Endocrine changes after laparoscopic ovarian cautery in polycystic ovarian syndrome. Am J Obstet Gynecol 1987, 156: 279–85.PubMedCrossRefGoogle Scholar
  42. 42.
    Mahesh VB, Brann DW. Regulation of the preovulatory gonadotropin surge by endogenous steroids. Steroids 1998, 63: 616–29.PubMedCrossRefGoogle Scholar
  43. 43.
    Hall JE, Taylor AE, Martin KA, Rivier J, Schoenfeld DA, Crowley WF Jr. Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women. Proc Natl Acad Sci U S A 1994, 91: 6894–8.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Smith PF, Frawley LS, Neill JD. Detection of LH release from individual pituitary cells by the reverse hemolytic plaque assay: estrogen increases the fraction of gonadotropes responding to GnRH. Endocrinology 1984, 115: 2484–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Young JR, Jaffe RB. Strength-duration characteristics of estrogen effects on gonadotropin response to gonadotropin-releasing hormone in women. II. Effects of varying concentrations of estradiol. J Clin Endocrinol Metab 1976, 42: 432–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Morales AJ, Laughlin GA, Butzow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 1996, 81: 2854–64.PubMedGoogle Scholar
  47. 47.
    Grulet H, Hecart AC, Delemer B et al. Roles of LH and insulin resistance in lean and obese polycystic ovary syndrome. Clin Endocrinol (Oxf) 1993, 38: 621–6.CrossRefGoogle Scholar
  48. 48.
    Dale PO, Tanbo T, Vaaler S, Abyholm T. Body weight, hyperinsulinemia, and gonadotropin levels in the polycystic ovarian syndrome: evidence of two distinct populations. Fertil Steril 1992, 58: 487–91.PubMedGoogle Scholar
  49. 49.
    Ke WX, Shan GQ, Hua SY. Different responses of insulin, C-peptide, and testosterone to an oral glucose tolerance test in two groups of women with polycystic ovarian syndrome. Acta Obstet Gynecol Scand 1996, 75: 166–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Banaszewska B, Spaczynski RZ, Pelesz M, Pawelczyk L. Incidence of elevated LH/FSH ratio in polycystic ovary syndrome women with normo-and hyperinsulinemia. Rocz Akad Med Bialymst 2003, 48: 131–4.PubMedGoogle Scholar
  51. 51.
    Toprak S, Yonem A, Cakir B, et al. Insulin resistance in nonobese patients with polycystic ovary syndrome. Horm Res 2001, 55: 65–70.PubMedCrossRefGoogle Scholar
  52. 52.
    Tropeano G, Vuolo IP, Lucisano A, et al. Gonadotropin levels in women with polycystic ovary syndrome: their relationship to body weight and insulin levels. J Endocrinol Invest 1996; 19: 139–45.PubMedCrossRefGoogle Scholar
  53. 53.
    Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987, 65: 499–507.PubMedCrossRefGoogle Scholar
  54. 54.
    Robinson S, Kiddy D, Gelding SV, et al. The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf) 1993, 39: 351–5.CrossRefGoogle Scholar
  55. 55.
    Sampson M, Kong C, Patel A, Unwin R, Jacobs HS. Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1996, 45: 623–9.CrossRefGoogle Scholar
  56. 56.
    Doi SA, Al-Zaid M, Towers PA, Scott CJ, Al-Shoumer KA. Irregular cycles and steroid hormones in polycystic ovary syndrome. Hum Reprod 2005, 20: 2402–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Patel K, Coffler MS, Dahan MH, et al. Increased luteinizing hormone secretion in women with polycystic ovary syndrome is unaltered by prolonged insulin infusion. J Clin Endocrinol Metab 2003, 88: 5456–61.PubMedCrossRefGoogle Scholar
  58. 58.
    Fulghesu AM, Cucinelli F, Pavone V, et al. Changes in luteinizing hormone and insulin secretion in polycystic ovarian syndrome. Hum Reprod 1999, 14: 611–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004; 59: 141–54.PubMedCrossRefGoogle Scholar
  60. 60.
    Gambineri A, Pelusi C, Genghini S, et al. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2004, 60: 241–9.CrossRefGoogle Scholar
  61. 61.
    Sattar N, Hopkinson ZE, Greer IA. Insulin-sensitising agents in polycystic-ovary syndrome. Lancet 1998, 351: 305–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Seli E, Duleba AJ. Should patients with polycystic ovarian syndrome be treated with metformin? Hum Reprod 2002, 17: 2230–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Loverro G, Lorusso F, De Pergola G, Nicolardi V, Mei L, Selvaggi L. Clinical and endocrinological effects of 6 months of metformin treatment in young hyperinsulinemic patients affected by polycystic ovary syndrome. Gynecol Endocrinol 2002, 16: 217–24.PubMedCrossRefGoogle Scholar
  64. 64.
    Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997, 82: 2108–16.PubMedGoogle Scholar
  65. 65.
    Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y, Kurabayashi T, Tanaka K. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome. Fertil Steril 1999, 71: 323–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Buyalos RP, Geffner ME, Watanabe RM, Bergman RN, Gornbein JA, Judd HL. The influence of luteinizing hormone and insulin on sex steroids and sex hormone-binding globulin in the polycystic ovarian syndrome. Fertil Steril 1993, 60: 626–33.PubMedGoogle Scholar
  67. 67.
    Diamond MP, Grainger DA, Laudano AJ, Starick-Zych K, De-Fronzo RA. Effect of acute physiological elevations of insulin on circulating androgen levels in nonobese women. J Clin Endocrinol Metab 1991, 72: 883–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Doi SA, Towers PA, Scott CJ, Al-Shoumer KA. PCOS: an ovarian disorder that leads to dysregulation in the hypothalamic-pituitary-adrenal axis? Eur J Obstet Gynecol Reprod Biol 2005, 118: 4–16.PubMedCrossRefGoogle Scholar
  69. 69.
    Bergh C, Carlsson B, Olsson JH, Selleskog U, Hillensjo T. Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin. Fertil Steril 1993, 59: 323–31.PubMedGoogle Scholar
  70. 70.
    Holte J, Bergh T, Gennarelli G, Wide L. The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women. Clin Endocrinol (Oxf) 1994, 41: 473–81.CrossRefGoogle Scholar
  71. 71.
    Dunaif A, Mandeli J, Fluhr H, Dobrjansky A. The impact of obesity and chronic hyperinsulinemia on gonadotropin release and gonadal steroid secretion in the polycystic ovary syndrome. J Clin Endocrinol Metab 1988, 66: 131–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Silfen ME, Denburg MR, Manibo AM, et al. Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents. J Clin Endocrinol Metab 2003, 88: 4682–8.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2005

Authors and Affiliations

  • S. A. R. Doi
    • 1
  • M. Al-Zaid
    • 2
  • P. A. Towers
    • 3
  • C. J. Scott
    • 3
  • K. A. S. Al-Shoumer
    • 1
  1. 1.Division of Endocrinology, Mubarak Al-Kabeer Hospital and Department of Medicine, Faculty of MedicineKuwait UniversityShuwaikh, KuwaitKuwait
  2. 2.Radioimmunoassay LaboratoryMubarak Al-Kabeer HospitalKuwait
  3. 3.School of Biomedical SciencesCharles Sturt UniversityAustralia

Personalised recommendations