Skip to main content
SpringerLink
Log in

Ovarian Dysfunction in Peripubertal Hyperinsulinemia

  • Original Articles
  • Published:
The Journal of the Society for Gynecologic Investigation: JSGI Aims and scope Submit manuscript

Abstract

Objective

Increasing evidence suggests that hyperinsulinemia plays an important role in the patho-genesis of polycystic ovary syndrome (PC OS). However, the timing for the onset of hyperinsulinemia is not clear. The objective of this study was to examine the effect of peripubertal hyperinsulinemia on the maturing female reproductive axis.

Methods

Hyperinsulinemia was induced in 28-day-old peripubertal female rats by infusing insulin (0.04 IU/d) via subcutaneously implanted Alzet minipumps (Model #2004; Durect Corp, Cupertino, CA; constant flow rate 0.25 μL/h)for 4 weeks. Control animals were administered normal saline. Estrus cyclicity was monitored regularly. Upon termination of the experimental period, the animals were killed, trunk blood and pituitaries were collected for hormone assays, and ovaries were collected for histological and immunocytochemical studies.

Results

In contrast to the control animals, hyperinsulinemic animals had (1) erratic estrus cycles, with prolonged (2 to 3 days) metestrus-diestrus or diestrus-proestrus stages; (2) significantly (P <. 05) decreased levels of serum progesterone, and significantly (P <.05) increased levels of serum testosterone and dehydroepiandrostene sulfate; (3) prematurely luteinized ovarian follicles with prominent thecal and interfollicular stromal proliferation; and (4) markedly reduced expression of growth differentiation factor-9 (GDF-9) and activin receptors (ActR) I and IB in the ovaries.

Conclusion

Peripubertal hyperinsulinemia in rats causes hormonal and ovarian changes similar to those in women with PCOS. Based on these novel findings, we speculate that peripubertal hyperinsulinemia may be a risk factor for the development of PCOS later in life. (J Soc Gynecol Investig 2006;13: 122–9) Copyright © 2006 by the Society for Gynecologic Investigation.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Homburg R. Polycystic ovary syndrome-From gynaecological curiosity to multisystem endocrinopathy. Human Reprod 1996;11:29–39.

    Article  CAS  Google Scholar 

  2. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperan-drogenism and hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980;50:113–6.

    Article  CAS  PubMed  Google Scholar 

  3. Chang RJ, Nakamura RM, Judd HL, Kaplan SA. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 1983;57:356–9.

    Article  CAS  PubMed  Google Scholar 

  4. Dunaif A. Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis. Endocr Rev 1997;18:774–800.

    CAS  PubMed  Google Scholar 

  5. Pinhas-Hamiel O, Dolan L, Daniels S, Standiford D, Khoury P, Zeitler P. Increased incidence of non-insulin dependent diabetes mellitus among adolescents. J Pediatr 1996;128:608–15.

    Article  CAS  PubMed  Google Scholar 

  6. Glaser N, McFeely M, Jones K. Non-insulin dependent diabetes mellitus in childhood. J Investig Med 1995;43:134A.

    Google Scholar 

  7. Sinha R, Fisch G, Teague B. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 2002;346:802–10.

    Article  CAS  PubMed  Google Scholar 

  8. Ibanez L, de Zegher F, Potau N. Premature pubarche, ovarian hyperandrogenism, hyperinsulinism and the polycycstic ovary syndrome: From a complex constellation to a simple sequence of prenatal onset. J Endocrinol Invest 1998;21:558–66.

    Article  CAS  PubMed  Google Scholar 

  9. Franks S. Adult polycystic ovary syndrome begins in childhood. Best Pract Res Clin Endocrinol 2002;16:263–72.

    Article  Google Scholar 

  10. Chatterjee-Chakrabarty S, Miller BT, Collins TJ, Nagamani M. Adverse effects of methylphenidate on the reproductive axis of adolescent female rats. Fertil Steril 2005;84:1131–8.

    Article  CAS  PubMed  Google Scholar 

  11. Juan CC, Shen YW, Chien Y, Lin YJ, Chang SF, Ho LT. Insulin infusion induces endothelin-1-dependent hypertension in rats. Am J Physiol Endocrinol Metab 2004;287:E948–54.

    Article  CAS  PubMed  Google Scholar 

  12. Juan CC, Fang VS, Kwok CF, Perng JC, Chou YC, Ho LT. Exogenous hyperinsulinemia causes insulin resistance, hyperen-dothelinemia and subsequent hypertension in rats. Metabolism 1999;48:465–71.

    Article  CAS  PubMed  Google Scholar 

  13. Boucher J, Masri B, Daviaud D, et al. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 2005;146:1764–71.

    CAS  PubMed  Google Scholar 

  14. Parkening TA, Collins TJ, Smith ER. Plasma and pituitary concentrations of LH, FSH and prolactin in aged female C57BL/6 mice. J Reprod Fertil 1980;58:377–86.

    Article  CAS  PubMed  Google Scholar 

  15. Chatterjee S, Gangula PPR, Dong TL, Yallampalli C. Immuno-cytochemical localization of nitric oxide synthase-III in reproductive organs of female rats during the estrus cycle. Histochem J 1996;28:715–23.

    Article  CAS  PubMed  Google Scholar 

  16. Fang L, Chatterjee S, Dong YL, Gangula PPR, Yallampalli C. Immunohistochemical localization of constitutive and inducible cyclooxygenases in rat uterus during the estrous cycle and pregnancy. Histochem J 1998;30:383–91.

    Article  CAS  PubMed  Google Scholar 

  17. O’Dnscoll SW, Marx RG, Baton DE, Miura Y, Gallay SH, Fitzsimons JS. Validation of a simple histological-histo-chemical cartilage scoring-system. Tissue Engineering 2001;7:313–20.

    Article  Google Scholar 

  18. The 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.

    Google Scholar 

  19. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent obesity in the polycystic ovary syndrome. Diabetes 1989;38:1165–74.

    Article  CAS  PubMed  Google Scholar 

  20. Nestler JE, Clore JN, Blackard WG. The central role of obesity (hyperinsulinemia) in the pathogenesis of the polycystic ovary syndrome. Am J Obstet Gynecol 1989;161:1095–7.

    Article  CAS  PubMed  Google Scholar 

  21. O’Meara NM, Blackman JD, Ehrmann DA. Defects in beta-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1993;76:1241–7.

    PubMed  Google Scholar 

  22. Ibanez L, Potau N, Georgopoulos N, Prat N, Gussinye M, Carrascosa A. Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandro-genism. J Clin Endocrinol Metab 1996;81:1237–43.

    CAS  PubMed  Google Scholar 

  23. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223–36.

    Article  CAS  PubMed  Google Scholar 

  24. Mauras N, Veldhuis JD, Haymond MW, Rogol AD. Sex steroids, growth hormone, insulin-like growth factor-1: Neuroendocrine and metabolic regulation in puberty. Horm Res 1996;45:74–80.

    Article  CAS  PubMed  Google Scholar 

  25. Meller WH, Grambasch PL, Bingham C, Tagtaz GE. Hypothalamic pituitary gonadal axis dysregulation in depressed women. Psychoneuroendocrinology 2001;26:253–9.

    Article  CAS  PubMed  Google Scholar 

  26. Burger HG, Dudley E, Mamers P, Robertson D, Groome N, Dennerstein L. The ageing female reproductive axis I. Novartis Foundation Symposium 2002;242:161–7.

    CAS  PubMed  Google Scholar 

  27. Sessions DR, Reedy SE, Vick MM, Murphy BA, Fitzgerald BP. Development of a model for inducing transient insulin resistance in the mare: Preliminary implications regarding the estrous cycle. J Anim Sci 2004;82:2321–8.

    Article  CAS  PubMed  Google Scholar 

  28. Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 1989;83:23–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647–54.

    Article  CAS  PubMed  Google Scholar 

  30. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin sensitizing agent troglitazone: A novel therapy for the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:3299–306.

    CAS  PubMed  Google Scholar 

  31. Nagamani M, Lingold JC, Gomez L. Clinical and hormonal studies in hyperthecosis of the ovaries. Fertil Steril 1981;36:326–32.

    Article  CAS  PubMed  Google Scholar 

  32. Nagamani M. PCO variants: Hyperthecosis. In: Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive endocrinology, surgery and technology. New York: Raven, 1996:1258–69.

    Google Scholar 

  33. Stuart CA, Nagamani M. Acute augmentation of plasma androstenedione and dehydroepiandrosterone by euglycemic insulin infusion: Evidence for a direct effect of insulin on ovarian steroidogenesis. In: Hazeltine F, Duaniff A, eds. Polycystic ovarian disease. Cambridge: Blackwell Scientific, 1992:279–88.

    Google Scholar 

  34. Sepilian V, Nagamani M. Effects of rosigliatzone in obese women with polycystic ovary syndrome and severe insulin resistance. J Clin Endocrinol Metab 2005;90:60–5.

    Article  CAS  PubMed  Google Scholar 

  35. Hines GA, Smith EF, Azziz R. Influence of insulin and testos-terone on adrenocortical steroidogenesis in vitro: Preliminary studies. Fertil Steril 2001;76:730–5.

    Article  CAS  PubMed  Google Scholar 

  36. Dong J, Albertini DF, Nishimori K, Kumar TR, Lu N, Matzuk MM. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 1996;383:531–5.

    Article  CAS  PubMed  Google Scholar 

  37. Elvin JA, Yan C, Wang P, Nishimori K, Matzuk MM. Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary. Mol Endocrinol 1999;13:1018–34.

    Article  CAS  PubMed  Google Scholar 

  38. Matzuk MM. Revelations of ovarian follicle biology from gene knockout mice. Mol Cell Endocrinol 2000;163:61–6.

    Article  CAS  PubMed  Google Scholar 

  39. Filho FLT, Baracat EC, Lee TH, et al. Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:1337–44.

    Article  Google Scholar 

  40. Peng C, Mukai ST. Activins and their receptors in female reproduction. Cell Biol 2000;78:261–79.

    CAS  Google Scholar 

  41. Pangas SA, Rademaker AWFDA, Woodruff TK. Localization of activin signal transduction components in normal human ovarian follicles: implications for autocrine and paracrine signaling in the ovary. J Clin Endocrinol Metab 2002;87:2644–57.

    Article  CAS  PubMed  Google Scholar 

  42. Duleba AJ, Pehlivan T, Carbone R, Spaczynski RZ. Activin stimulates proliferation of rat ovarian thecal-interstitial cells. Biol Reprod 2001;65:704–9.

    Article  CAS  PubMed  Google Scholar 

  43. Roberts VJ, Barth S, el-Roeiy A, Yen SS. Expression of inhibin/ activin system messenger ribonucleic acids and proteins in ovarian follicles from women with polycystic ovarian syndrome. J Clin Endocrinol Metab 1994;79:1434–9.

    CAS  PubMed  Google Scholar 

  44. Sawetawan C, Carr BR, McGee E, Bird IM, Hong TL, Rainey WE. Inhibin and activin differentially regulate androgen production and 17 alpha-hydroxylase expression in human ovarian thecal-like tumor cells. J Endocrinol 1996;148:213–21.

    Article  CAS  PubMed  Google Scholar 

  45. Yamoto M, Minami S, Nakano R. Immunohistochemical localization of inhibin subunits in polycystic ovary. J Clin Endocrinol Metab 1993;77:859–62.

    CAS  PubMed  Google Scholar 

  46. Dewailly D. Physiopathology of polycystic ovary syndrome. Ann Endocrinol 1999;60:123–30.

    CAS  Google Scholar 

  47. Urbanek M, Legro RS, Driscoll DA, et al. Thirty-seven candidate genes for polycystic ovary syndrome: Strongest evidence for linkage is with follistatin. Proc Nad Acad Sci U S A 1999;96:8573–8.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Blvd, Galveston, Texas, 77555, USA

    Shilla Chakrabarty PhD, Brian T. Miller PhD, Thomas J. Collins PhD & Manubai Nagamani MD

  2. Department of Neurosciences and Cell Biology, University of Texas Medical Branch, Galveston, Texas, 77555, USA

    Shilla Chakrabarty PhD, Brian T. Miller PhD, Thomas J. Collins PhD & Manubai Nagamani MD

Authors
  1. Shilla Chakrabarty PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian T. Miller PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas J. Collins PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manubai Nagamani MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shilla Chakrabarty PhD.

Additional information

Supported in part by a grant to S.C. from the Center for Interdisciplinary Research in Women’s Health.

The authors acknowledge the Ligand Assay and Analysis Core Laboratory of the University of Virginia at Charlottesville, VA, for measurements of FSH and LH levels. They also thank the Publication, Grant, and Media Support area of the Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, TX, for their help in preparing the manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chakrabarty, S., Miller, B.T., Collins, T.J. et al. Ovarian Dysfunction in Peripubertal Hyperinsulinemia. Reprod. Sci. 13, 122–129 (2006). https://doi.org/10.1016/j.jsgi.2005.11.005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.jsgi.2005.11.005

Key words

Search

Navigation