Skip to main content
Log in

Insights into hypothalamic-pituitary dysfunction in polycystic ovary syndrome

  • Views on Pathogenetic Mechanisms
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Polycystic ovary syndrome (PCOS) is characterized by menstrual dysfunction and hyperandrogenism in the absence of other known causes. While the pathogenesis of PCOS remains elusive and is likely to involve abnormalities in several systems, there has long been an association of abnormal gonadotropin secretion with this disorder. In recent studies we have determined that 94% of women meeting the broad criteria for PCOS have an increased LH/FSH ratio. Several lines of evidence suggest that the mechanisms underlying the increased LH/FSH ratio in PCOS include an increased frequency of GnRH secretion. Decreased sensitivity to progesterone negative feedback on the GnRH pulse generator may play a role in this neuroendocrine defect. Additional factors which may contribute to the low to normal FSH levels in the face of increased LH include chronic mild estrogen increases and possibly inhibin. In addition to these effects on the differential control of FSH, there is increased pituitary sensitivity of LH secretion to GnRH. Both estrogen and androgens have been proposed as candidates mediating these effects. Superimposed on these underlying abnormalities in gonadotropin secretion is a marked inhibitory effect of obesity on LH secretion which may be mediated at either a pituitary or hypothalamic level.

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.

Similar content being viewed by others

References

  1. Stein I., Leventhal M. Amenorrhea associated with bilateral polycystic ovaries. Am. J. Obstet. Gynecol. 29: 181, 1935.

    Google Scholar 

  2. McArthur J.W., Ingersoll F.M., Worcester J. The urinary excretion of interstitial cell and follicle-stimulating hormone activity by women with diseases of the reproductive system. J. Clin. Endocrinol. Metab. 18: 1202, 1958.

    Article  PubMed  CAS  Google Scholar 

  3. Yen S.S.C., Vela P., Rankin J. Inappropriate secretion of follicle stimulating hormone and luteinizing hormone in polycystic ovarian disease. J. Clin. Endocrinol. Metab. 30: 435, 1970.

    Article  PubMed  CAS  Google Scholar 

  4. Anttila L., Ding Y.-Q., Ruutiainen K., Erkkola R., Irjala K., Huhtaniemi I. Clinical features and circulating gonadotropin, insulin, and androgen interactions in women with polycystic ovarian disease. Fertil. Steril. 55: 1057, 1991.

    PubMed  CAS  Google Scholar 

  5. Fauser B.C.J.M., Pache T.D., Lamberty W.J., et al. Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease. J. Clin. Endocrinol. Metab. 73: 811, 1991.

    Article  PubMed  CAS  Google Scholar 

  6. Lobo R.A., Kletzky O.A., Campeau J.D., di Zerega G.S. Elevated bioactive luteinizing hormone in women with the polycystic ovary syndrome. Fertil. Steril. 39: 674, 1983.

    PubMed  CAS  Google Scholar 

  7. Rebar R., Judd H.L., Yen S.S.C., Rakoff J., Vandenberg G., Naftolin F. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J. Clin. Invest. 57: 1320, 1976.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Conway G.S., Honour J.W., Jacobs H.S. Heterogeneity of the polycystic ovary syndrome: clinical, endocrine and ultrasound features in 556 patients. Clin. Endocrinol. 30: 459, 1989.

    Article  CAS  Google Scholar 

  9. Franks S. Polycystic ovary syndrome: a changing perspective. Clin. Endocrinol. (Oxf.) 31: 87, 1989.

    Article  CAS  Google Scholar 

  10. Yen S.S.C. The polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 12: 177, 1980.

    Article  CAS  Google Scholar 

  11. Zawadzki J.K., Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif, A., Givens J.R., Haseltine F.P., Merriam G.R. (Eds.), Polycystic Ovary Syndrome. Current Issues in Endocrinology and Metabolism. Blackwell Scientific Publications, Boston, 1992, p. 377.

    Google Scholar 

  12. Taylor A.E., McCourt B., Anderson E.J., Martin K.A., Adams J.M., Schoenfeld D., Hall J.E. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 82: 2248, 1997.

    PubMed  CAS  Google Scholar 

  13. Belchetz E.E., Plant T.M., Nakai Y., Keogh E.J., Knobil E. Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science 202: 631, 1978.

    Article  PubMed  CAS  Google Scholar 

  14. Conn P.M., Crowley W.F. Jr. Gonadotropin-releasing hormone and its analogues. N. Engl. J. Med. 324: 93, 1991.

    Article  PubMed  CAS  Google Scholar 

  15. Spratt D.I., Finkelstein J.S., Butler J.P., Badger T.M., Crowley W.F. Jr. Effects of increasing the frequency of low doses of gonadotropin-releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men. J. Clin. Endocrinol. Metab. 64: 1179, 1987.

    Article  PubMed  CAS  Google Scholar 

  16. Gross K.M., Matsumoto A.M., Bremner W.J. Differential control of luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone pulse frequency in man. J. Clin. Endocrinol. Metab. 64: 674, 1987.

    Article  Google Scholar 

  17. Finklestein J.S., Badger T.M., O’Dea St.L., Spratt D.I., Crowley W.F. Effects of decreasing the frequency of gonadotropin-releasing hormone stimulation on gonadotropin secretion in gonadotropin-releasing hormone-deficient men and perifused rat pituitary cells. J. Clin. Invest. 81: 1725, 1988.

    Article  Google Scholar 

  18. Dalkin A. C., Haisenleder D.J., Ortolano G.A., Ellis T.R., Marshall J.C. The frequency of gonadotropin-releasing hormone stimulation differentially regulates gonadotropin sub-unit messenger ribonucleic acid expression. Endocrinology. 125: 917, 1989.

    Article  PubMed  CAS  Google Scholar 

  19. Papavasiliou S.S., Zmeili S., Khoury S., Landefeld T.D., Chin W.W., Marshall J.C. Gonadotropin releasing hormone differentially regulates expression of the genes for luteinizing hormone alpha and beta subunits in male rats. Proc. Natl. Acad. Sci. 83: 4026, 1986.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Kaiser U.B., Sabbagh E., Katzenellenbogen R.A., Conn P.M., Chin W.W. A mechanism for the differential regulation of gonadotropin subunit gene expression by gonadotropin-releasing hormone. Proc. Natl. Acad. Sci. 92: 12280, 1995.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Besecke L.M., Guendner M.J., Schneyer A. L., Bauer-Dantoin A.C., Jameson J.L., Weiss J. Gonadotropin-releasing hormone regulated follicle-stimulating hormone-b gene expression through an activin/follistatin autocrine or paracrine loop. Endocrinology. 137: 3667, 1996.

    PubMed  CAS  Google Scholar 

  22. Gharib S.D., Wierman M.E., Shupnik M.A., Chin W.W. Molecular biology of the pituitary gonadotropins. Endocr. Rev. 11: 177, 1990.

    Article  PubMed  CAS  Google Scholar 

  23. Marshall J.C., Case G.D., Valk T.W., Corley K.P., Sauder S.E., Kelch R.P. Selective inhibition of follicle-stimulating hormone secretion by estradiol. J. Clin. Invest. 71: 248, 1983.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Keye W.R. Jr., Jaffe R.B. Strength-duration characteristics of estrogen effect on gonadotropin response to gonadotropin-releasing hormone. I. Effects of varying duration of estradiol administration. J. Clin. Endocrinol. Metab. 41: 1003, 1975.

    Article  PubMed  CAS  Google Scholar 

  25. DeKretser D.M., Robertson D.M. The isolation and physiology of inhibin and related proteins. Biol. Reprod. 40: 33, 1989.

    Article  CAS  Google Scholar 

  26. DePaolo L.V., Bickak T.A., Erickson G.F., Shimasaki S., Ling N. Follistatin and activin: a potential intrinsic regulatory system within diverse tissues. Proc. Soc. Exp. Biol. Med. 198: 500, 1991.

    Article  PubMed  CAS  Google Scholar 

  27. Khoury R.H., Wang Q.F., Crowley W.F. Jr, Hall J.E., Schneyer A.L., Toth T., Midgley A.R. Jr, Sluss P.M. Serum Follistatin levels in women: evidence against an endocrine function of ovarian follistatin. J. Clin. Endocrinol. Metab. 80: 1361, 1995.

    PubMed  CAS  Google Scholar 

  28. Waldstreicher J., Santoro N.F., Hall J.E., Filicori M., Crowley W.F. Hyperfunction of the hypothalamic-pituitary axis in women with Polycystic Ovarian Disease: Indirect evidence for partial gonadotroph desensitization. J. Clin. Endocrinol. Metab. 66: 165, 1988.

    Article  PubMed  CAS  Google Scholar 

  29. Burger C.W., Korsen T., van Kessel H., van Dop P.A., Caron F.J.M., Schoemaker J. Pulsatile luteinizing hormone patterns in the follicular phase of the menstrual cycle, polycystic ovarian disease (PCOD) and non-PCOD secondary amenorrhea. J. Clin. Endocrinol. Metab. 61: 1126, 1985.

    Article  PubMed  CAS  Google Scholar 

  30. Imse V., Holzapfel G., Hinney B., Kuhn W., Wuttke W. Comparison of luteinizing hormone pulsatility in the serum of women suffering from polycystic ovarian disease using a bioassay and five different immunoassays. J. Clin. Endocrinol. Metab. 74: 1053, 1992.

    PubMed  CAS  Google Scholar 

  31. 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. 66: 131, 1988.

    Article  PubMed  CAS  Google Scholar 

  32. Berga S.L., Guzick D.S., Winters S.J. Increased luteinizing hormone and alpha-subunit secretion in women with hyperandrogenic anovulation. J. Clin. Endocrinol. Metab. 77: 895, 1993.

    PubMed  CAS  Google Scholar 

  33. Crowley W.F., Taylor A.E., Martin K.A., Whitcomb R.W., Finkelstein J.S., Hall J.E. use of the free alpha subunit (FAS) of glycoprotein secreting hormones as a surrogate marker of GnRH secretion in the human. In: J.W. Lusbader, J.D. Puett, R. Ruddon (Eds.), Serono Glycoprotein Hormones: Structure, Function and Clinical Implications. Symposia, USA, pp. 253, 1994.

    Chapter  Google Scholar 

  34. Hall J.E., Taylor A.E., Martin K.A., Rivier J., Schoenfeld D., Crowley W.F. Jr. Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women. Proc. Natl. Acad. Sci. U.S.A. 91: 6894, 1994.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Hall J.E., Whitcomb R., Pralong F.P., Crowley W.F. Jr. Use of a GnRH antagonist to quantitate the amount of endogenous GnRH secreted: validation using GnRH-deficient men. The Endocrine Society 76th Annual Meeting Program and Abstracts 1994, 1525: 582.

    Google Scholar 

  36. Hayes F.J., Taylor A.E., Martin K.A., Hall J.E. Use of a GnRH antagonist as a physiologic probe in polycystic ovary syndrome: assessment of neuroendocrine and androgen dynamics. J. Clin. Endocrinol. Metab. 83: 2343, 1998.

    PubMed  CAS  Google Scholar 

  37. Corenthal L., Von Hagen S., Larkins D., Ibrahim J., Santoro N. Benefits of continuous physiological pulsatile gonadotropin-releasing hormone therapy in women with polycystic ovarian syndrome. Fertil. Steril. 61: 1027, 1994.

    PubMed  CAS  Google Scholar 

  38. Christman G.M., Randolph J.F., Kelch R.P., Marshall J.C. Reduction of gonadotropin-releasing hormone pulse frequency is associated with subsequent selective follicle-stimulating hormone secretion in women with polycystic ovarian disease. J. Clin. Endocrinol. Metab. 72: 1278, 1991.

    Article  PubMed  CAS  Google Scholar 

  39. Buckler H.M., Phillips S.E., Cameron I.T., Healy D.L., Burger H.G. Vaginal progesterone administration before ovulation induction with exogenous gonadotropins in polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 67: 300, 1988.

    Article  PubMed  CAS  Google Scholar 

  40. Daniels T.L., Berga S.L. Resistance of gonadotropin releasing hormone drive to sex steroid-induced suppression in hyperandrogenic anovulation. J. Clin. Endocrinol. Metab. 82: 4179, 1997.

    PubMed  CAS  Google Scholar 

  41. Pastor C.L., Griffin-Korf M.L., Aloi J.A., Evans W.S., Marshall J.C. Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J. Clin. Endocrinol. Metab. 83: 582, 1998.

    PubMed  CAS  Google Scholar 

  42. Zumoff B., Freeman F., Coupey S., et al. A chronobiologic abnormality in luteinizing hormone secretion in teenage girls with the polycystic-ovary syndrome. N. Engl. J. Med. 309: 1206, 1983.

    Article  PubMed  CAS  Google Scholar 

  43. Batrinos M.L. Diagnostic dilemmas in polycystic ovarian syndrome. In: Tolis G., Bringer J., Chrousos G.P. (Eds.) Intraovarian Regulators and Polycystic Ovarian Syndrome. Ann. NY Acad. Sci., Philadelphia, 687: 230, 1993.

    Google Scholar 

  44. Smith P.F., Frawley L.S., Neill J.D. Detection of LH release from individual pituitary cells by the reverse hemolytic plaque assay: estrogen increases the fraction of gonadotropes responding to GnRH. Endocrinology. 115: 2484, 1984.

    Article  PubMed  CAS  Google Scholar 

  45. DeVane G.W., Czekala N.M., Judd H.L., Yen S.S.C. Circulating gonadotropins, estrogens, and androgens in Polycystic Ovarian Disease. Am. J. Obstet. Gynecol. 121: 496, 1975.

    PubMed  CAS  Google Scholar 

  46. Lobo R.A., Granger L., Goebelsmann U., Mishell D.B. Elevations in unbound serum estradiol as a possible mechanism for inappropriate gonadotropin secretion in women with PCO. J. Clin. Endocrinol. Metab. 52: 156, 1981.

    Article  PubMed  CAS  Google Scholar 

  47. Chang R.J., Mandel F.P., Liu J.K.H., Judd H.L. Enhanced disparity of gonadotropin secretion by estrone in women with polycystic ovarian disease. J. Clin. Endocrinol. Metab. 54: 490, 1982.

    Article  PubMed  CAS  Google Scholar 

  48. Dunaif A., Scully R.E., Andersen R.N., et al. The effects of continuous androgen secretion on the hypothalamic-pituitary axis in women: evidence from a luteinized thecoma of the ovary. J. Clin. Endocrinol. Metab. 59: 389, 1984.

    Article  PubMed  CAS  Google Scholar 

  49. Finklestein J.S., Whitcomb R.W., O’Dea L. St. L., et al. Sex steroid control of gonadotropin secretion in the human male. In: Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men. J. Clin. Endocrinol. Metab. 73: 609, 1991.

    Article  Google Scholar 

  50. Serafini P., Silva P.D., Paulson R.J., et al. Acute modulation of the hypothalamic-pituitary axis by intravenous testosterone in normal women. Am. J. Obstet. Gynecol. 155: 1288, 1986.

    Article  PubMed  CAS  Google Scholar 

  51. Dunaif A. Do androgens directly regulate gonadotropin secretion in the Polycystic Ovary Syndrome? J. Clin. Endocrinol. Metab. 63: 215, 1986.

    Article  PubMed  CAS  Google Scholar 

  52. Spinder T., Spijkstra J.J., Gooren L.J.G., Hompes P.G.A., van Kessel H. Effects of long-term testosterone administration on gonadotropin secretion in agonadal female to male transsexuals compared with hypogonadal and normal women. J. Clin. Endocrinol. Metab. 68: 200, 1989.

    Article  PubMed  CAS  Google Scholar 

  53. Buckler H.M., McLachlan R.L., MacLachlan V.B., et al. Serum inhibin levels in polycystic ovary syndrome: basal levels and response to luteinizing hormone-releasing hormone agonist and exogenous gonadotropin administration. J. Clin. Endocrinol. Metab. 66: 798, 1988.

    Article  PubMed  CAS  Google Scholar 

  54. Pigny P., Desailloud R., Cortet-Rudelli C. et al. Serum α-inhibin levels in polycystic ovary syndrome: relationship to the serum androstenedione level. J. Clin. Endocrinol. Metab. 82: 1939, 1997.

    PubMed  CAS  Google Scholar 

  55. Lambert-Messerlian G.M., Hall J.E., Sluss P.M., Taylor A.E., Martin K.A., Groome N.P., Crowley W.F. Jr., Schneyer A.L. Relatively low levels of dimeric inhibin circulate in men and women with PCOS using a specific two-site ELISA. J. Clin. Endocrinol. Metab. 79: 45, 1994.

    PubMed  CAS  Google Scholar 

  56. Roberts V.J., Barth S., El-Roeiy A., Yen S.S.C. Expression of inhibin/activin subunits and follistatin messenger ribonucleic acids and proteins in ovarian follicles and the corpus luteum during the human menstrual cycle. J. Clin. Endocrinol. Metab. 77: 1402, 1993.

    PubMed  CAS  Google Scholar 

  57. Roberts V.J., Barth S., El-Roeiy A., Yen S.S.C. Expression of inhibin/activin system mRNAs and proteins in ovarian follicles from women with PCOS. J. Clin. Endocrinol. Metab. 79: 1434, 1994.

    PubMed  CAS  Google Scholar 

  58. Lockwood G.M., Muttukrishna S., Groome N.P., Matthews D.R., Ledger W.L. Mid-follicular phase pulses of inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle. J. Clin. Endocrinol. Metab. 83: 1730, 1998.

    Article  PubMed  CAS  Google Scholar 

  59. Hall J.E., Taylor A.E., Martin K.A., Adams J.M., Khoury R., Schneyer A.L., Sluss P.M., Crowley W.F. Jr. Inhibin B in polycystic ovarian syndrome (PCOS). 10th International Congress of Endocrinology, San Francisco Program and Abstracts 560: P2–624, 1996.

    Google Scholar 

  60. Lambert-Messerlian G., Taylor A., Leykin L. Characterization of intrafollicular steroid hormones, inhibin, and follistatin in women with and without polycystic ovarian syndrome following gonadotropin hyperstimulation. Biol. Reprod. 57: 1211, 1997.

    Article  PubMed  CAS  Google Scholar 

  61. Paradisi R., Venturoli S., Pasquali R., Capelli M., Porcu E., Fabbri R., Flamigni C. Effects of obesity on gonadotropin secretion in patients with polycystic ovarian disease. J. Endocrinol. Invest. 9: 139, 1986.

    Article  PubMed  CAS  Google Scholar 

  62. Kiddy D.S., Sharp P.S., White D.M., Scanion M.F., Mason H.D., Bray C.S., Poison D.W., Reed M.J., Franks S. Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: An analysis of 263 consecutive cases. Clin. Endocrinol. 32: 213, 1990.

    Article  CAS  Google Scholar 

  63. Morales A.J., Laughlin G.A., Butzow T., Maheshwari H., Baumann G., Yen S.S.C. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J. Clin. Endocrinol. Metab. 81: 2854, 1996.

    PubMed  CAS  Google Scholar 

  64. Arroyo A., Laughlin G.A., Morales A.J., Yen S.S.C. Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. J. Clin. Endocrinol. Metab. 82: 3718, 1997.

    Google Scholar 

  65. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr. Rev. 18: 774, 1997.

    PubMed  CAS  Google Scholar 

  66. Adashi E.Y., Hsueh A.J.W., Yen S.S.C. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology. 108: 1441, 1981.

    Article  PubMed  CAS  Google Scholar 

  67. Flier J.S. What’s in a name? In search of leptin’s physiologic role. J. Clin. Endocrinol. Metab. 83: 1407, 1998.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

This work was supported by U54-HD-29164, P30-HD-28138 and M01-RR 01066.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hall, J.E., Taylor, A.E., Hayes, F.J. et al. Insights into hypothalamic-pituitary dysfunction in polycystic ovary syndrome. J Endocrinol Invest 21, 602–611 (1998). https://doi.org/10.1007/BF03350785

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03350785

Key-words

Navigation