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Pathogenesis of Hyperandrogenism in Polycystic Ovary Syndrome

  • Wendy Y. Chang
  • Ricardo Azziz
Part of the Contemporary Endocrinology book series (COE)

Summary

Androgen excess (AE) is an important, even essential feature of the polycystic ovary syndrome (PCOS), and arises primarily from ovarian AE, although a hyperactivity of adrenocortical function and adrenal androgen (AA) excess are present in a significant number of patients. Increased ovarian theca cell function, and possibly number, and augmented expression of steroidogenic enzymes have been demonstrated in PCOS. Increased LH stimulation of thecal androgen biosynthesis also appears to be an important, early event in PCOS. Abnormalities in other intrinsic ovarian factors such as inhibin, activin, and follistatin appear to modulate ovarian LH response. Granulosa cell dysfunction may also contribute, with PCOS women demonstrating arrested granulose development and increased 5α-reductase expression. Adrenal AE, possibly arising from generalized adrenocortical hyper-responsivity, is a relatively common feature of PCOS. Finally, the metabolic consequences of obesity and insulin resistance appear to potentiate excess androgen production in adolescent and adult PCOS patients. In short, the hyperandrogenism of PCOS appears to be aptly multifactorial, consistent with the complex nature of the syndrome itself.

Key Words

Adrenal androgens polycystic ovary syndrome hirsutism luteinizing hormone insulin 

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References

  1. 1.
    Zawadski J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Given J, Haseltine F, Merriam G, eds. Polycystic Ovary Syndrome. Cambridge, MA: Blackwell Scientific Publications, 1992:377.Google Scholar
  2. 2.
    Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41.Google Scholar
  3. 3.
    Azziz R. Diagnostic criteria for polycystic ovary syndrome: a reappraisal. Fertil Steril 2005;83:1343.PubMedCrossRefGoogle Scholar
  4. 4.
    Rosenfield RL. Ovarian and adrenal function in polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:265.PubMedCrossRefGoogle Scholar
  5. 5.
    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 USA 1998;95:14956.PubMedCrossRefGoogle Scholar
  6. 6.
    Azziz R, Sanchez LA, Knochenhauer ES, Moran C, Lazenby J, Stephens KC, Taylor K, Boots LR. Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab 2004;89:453–62.PubMedCrossRefGoogle Scholar
  7. 7.
    Balen AH, Schachter ME, Montgomery D, Reid RW, Jacobs HS. Polycystic ovaries are a common finding in untreated female to male transsexuals. Clin Endocrinol (Oxf) 1993;38:325–9.Google Scholar
  8. 8.
    Abbott DH, Dumesic DA, Eisner JR, Colman RJ, Kemnitz JW. Insights into the development of PCOS from studies of prenatally androgenized female rhesus monkeys. Trends Endocrinol Metab 1998;9:62–7.CrossRefPubMedGoogle Scholar
  9. 9.
    DeVane GW, Czekala NM, Judd HL, Yen SS. Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol 1975;121:496.PubMedGoogle Scholar
  10. 10.
    Erickson GF, Magoffin DA, Dyer CA, Hofeditz C. The ovarian androgen producing cells: a review of structure/function relationships. Endocr Rev 1985;6:371–99.PubMedCrossRefGoogle Scholar
  11. 11.
    Apter D, Butzow T, Laughlin GA, Yen SS. Accelerated 24-hour luteinizing hormone pulsatile activity in adolescent girls with ovarian hyperandrogenism: relevance to the developmental phase of polycystic ovarian syndrome. J Clin Endocrinol Metab 1994;79:119–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Patton WC, Berger MJ, Thompson IE, Chong AP, Grimes EM, Taymor ML. Pituitary gonadotropin responses to synthetic luteinizing hormone-releasing hormone in patients with typical and atypical polycystic ovary disease. Am J Obstet Gynecol 1975;121:382–6.PubMedGoogle Scholar
  13. 13.
    Eagleson CA, Gingrich M, Pastor C, et al. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the GnRH pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 2000;85:4047.PubMedCrossRefGoogle Scholar
  14. 14.
    Tapanainen JS, Koivunen R, Fauser BC, et al. A new contributing factor to polycystic ovary syndrome: the genetic variant of luteinizing hormone. J Clin Endocrinol Metab 1999; 84:1711.PubMedCrossRefGoogle Scholar
  15. 15.
    Barnes RB, Rosenfield RL, Burstein S, Ehrmann DA. Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med 1989;320:559–65.PubMedCrossRefGoogle Scholar
  16. 16.
    Bruning JC, Gautam D, Burks DJ, et al. Role of brain insulin receptor in control of body weight and reproduction. Science 2000;289:2122.PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenfield Rl. Ovarian and adrenal function in polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:265.PubMedCrossRefGoogle Scholar
  18. 18.
    Chang RJ, Laufer LR, Meldrum DR, DeFazio J, Lu JK, Vale WW, Rivier JE, Judd HL. Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 1983;56:897–903.PubMedGoogle Scholar
  19. 19.
    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
  20. 20.
    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.PubMedCrossRefGoogle Scholar
  21. 21.
    Mahajan DK. Steroidogenesis in human polycystic ovary. Endocrinol Metab Clin North Am 1988;17:751–69.PubMedGoogle Scholar
  22. 22.
    Jakimiuk AJ, Weitsman SR, Navab A, Magoffin DA. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in theca and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab 2001;8:1318–23.CrossRefGoogle Scholar
  23. 23.
    Nelson VL, Legro RS, Strauss JF III, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol 1999;13:946–57.PubMedCrossRefGoogle Scholar
  24. 24.
    Wickenheisser JK, Nelson-Degrave VL, McAllister JM. Dysregulation of cytochrome P450 17alpha-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:1720–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Agarwal SK, Judd HL, Magoffin DA. A mechanism for suppression of estrogen production in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:3686–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Gregory SJ, Kaiser UB. Regulation of gonadotropins by inhibin and activin. Semin Reprod Med 2004; 22:253.PubMedCrossRefGoogle Scholar
  27. 27.
    Hsueh AJ, Dahl KD, Vaughan J, et al. Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis. Proc Natl Acad Sci USA 1987;84:5082.PubMedCrossRefGoogle Scholar
  28. 28.
    Norman RJ, Milner CR, Groome NP, Robertson DM. Circulating follistatin concentrations are higher and activin concentrations are lower in polycystic ovarian syndrome. Hum Reprod 2001;16:668.PubMedCrossRefGoogle Scholar
  29. 29.
    Anderson RA, Groome NP, Baird DT. Inhibin A and inhibin B in women with polycystic ovarian syndrome during treatment with FSH to induce mono-ovulation. Clin Endocrinol (Oxf) 1998; 48:577.CrossRefGoogle Scholar
  30. 30.
    Elting MW, Kwee J, Schats R, et al. The rise of estradiol and inhibin B after acute stimulation with follicle-stimulating hormone predict the follicle cohort size in women with polycystic ovary syndrome, regularly menstruating women with polycystic ovaries, and regularly menstruating women with normal ovaries. J Clin Endocrinol Metab 2001;86:1589.PubMedCrossRefGoogle Scholar
  31. 31.
    Wild RA, Umstot ES, Andersen RN, Ranney GB, Givens JR. Androgen parameters and their correlation with body weight in one hundred thirty-eight women thought to have hyperandrogenism. Am J Obstet Gynecol 1983;146:602–6.PubMedGoogle Scholar
  32. 32.
    Hoffman DL, Klove K, Lobo RA. The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women. Fertil Steril 1984;42:76–81.PubMedGoogle Scholar
  33. 33.
    Steinberger E, Smith KD, Rodriguez-Rigau LJ. Testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate in hyperandrogenic women. J Clin Endocrinol Metab 1984;59:471–7.PubMedGoogle Scholar
  34. 34.
    Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 1992;167:1807–12.PubMedGoogle Scholar
  35. 35.
    Kumar A, Woods KS, Bartolucci AA, Azziz R. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2005;62:644–9.CrossRefGoogle Scholar
  36. 36.
    Piltonen T, Koivunen R, Perheentupa A, Morin-Papunen L, Ruokonen A, Tapanainen JS. Ovarian age-related responsiveness to human chorionic gonadotropin in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;89:3769–75.PubMedCrossRefGoogle Scholar
  37. 37.
    Rosenfield RL, Barnes RB, Ehrmann DA. Studies of the nature of 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1994;79:1686–92.PubMedCrossRefGoogle Scholar
  38. 38.
    Miller D, Emans SJ, Kohane I. Follow-up study of adolescent girls with a history of premature pubarche. J Adolesc Health 1996;18:301–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Ibanez L, Potau N, Virdis R, Zampolli M, Terzi C, Gussinye M, Carrascosa A, Vicens-Calvet E. Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1993;76:1599–603.PubMedCrossRefGoogle Scholar
  40. 40.
    Ibanez L, Potau N, Zampolli M, Street ME, Carrascosa A. Girls diagnosed with premature pubarche show an exaggerated ovarian androgen synthesis from the early stages of puberty: evidence from gonadotropin-releasing hormone agonist testing. Fertil Steril 1997;67:849–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Meas T, Chevenne D, Thibaud E, Leger J, Cabrol S, Czernichow P, Levy-Marchal C. Endocrine consequences of premature pubarche in post-pubertal Caucasian girls. Clin Endocrinol (Oxf) 2002;57:101–6.CrossRefGoogle Scholar
  42. 42.
    Lobo RA, Goebelsmann U, Horton R. Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 1983;57:393–7.PubMedGoogle Scholar
  43. 43.
    Levin JH, Carmina E, Lobo RA. Is the inappropriate gonadotropin secretion of patients with polycystic ovary syndrome similar to that of patients with adult-onset congenital adrenal hyperplasia? Fertil Steril 1991;56:635–40.PubMedGoogle Scholar
  44. 44.
    Carmina E, Lobo RA. Ovarian suppression reduces clinical and endocrine expression of late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Fertil Steril 1994;62:738–43.PubMedGoogle Scholar
  45. 45.
    Dewailly D, Vantyghem-Haudiquet MC, Sainsard C, Buvat J, Cappoen JP, Ardaens K, Racadot A, Lefebvre J, Fossati P. Clinical and biological phenotypes in late-onset 21-hydroxylase deficiency. J Clin Endocrinol Metab 1986;63:418–23.PubMedGoogle Scholar
  46. 46.
    Moran C, Azziz R, Carmina E, Dewailly D, Fruzzetti F, Ibanez L, Knochenhauer ES, Marcondes JA, Mendonca BB, Pignatelli D, Pugeat M, Rohmer V, Speiser PW, Witchel SF. 21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study. Am J Obstet Gynecol 2000;183:1468–74.PubMedCrossRefGoogle Scholar
  47. 47.
    Azziz R, Black V, Hines GA, Fox LM, Boots LR. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 1998;83:2317–23.PubMedCrossRefGoogle Scholar
  48. 48.
    Moran C, Potter HD, Reyna R, Boots LR, Azziz R. Prevalence of 3beta-hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia in hyperandrogenic women with adrenal androgen excess. Am J Obstet Gynecol 1999;181:596–600.PubMedCrossRefGoogle Scholar
  49. 49.
    Moran C, Reyna R, Boots LS, Azziz R. Adrenocortical hyperresponsiveness to corticotropin in polycystic ovary syndrome patients with adrenal androgen excess. Fertil Steril 2004;81:126–31.PubMedCrossRefGoogle Scholar
  50. 50.
    Azziz R, Bradley EL, Jr, Potter HD, Boots LR. 3beta-hydroxysteroid dehydrogenase deficiency in hyperandrogenism. Am J Obstet Gynecol 1993;168:889–95.PubMedGoogle Scholar
  51. 51.
    Azziz R, Gay FL, Potter SR, Bradley E Jr, Boots LR. The effects of prolonged hypertestosteronemia on adrenocortical biosynthesis in oophorectomized women. J Clin Endocrinol Metab 1991;72: 1025–30.PubMedGoogle Scholar
  52. 52.
    Witchel SF, Kahsar-Miller M, Aston CE, White C, Azziz R. Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess. Fertil Steril 2005;83:371–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Azziz R, Wells G, Zacur HA, Acton RT. Abnormalities of 21-hydroxylase gene ratio and adrenal steroidogenesis in hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to acute adrenal stimulation. J Clin Endocrinol Metab 1991;73:1327–31.PubMedGoogle Scholar
  54. 54.
    Azziz R, Bradley EL Jr, Potter HD, Boots LR. Adrenal androgen excess in women: lack of a role for 17-hydroxylase and 17,20-lyase dysregulation. J Clin Endocrinol Metab 1995;80:400–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Joehrer K, Geley S, Strasser-Wozak EM, Azziz R, Wollmann HA, Schmitt K, Kofler R, White PC. CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Hum Mol Genet 1997;6:1829–34.PubMedCrossRefGoogle Scholar
  56. 56.
    Lutfallah C, Wang W, Mason JI, Chang YT, Haider A, Rich B, Castro-Magana M, Copeland KC, David R, Pang S. Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 2002;87:2611–22.PubMedCrossRefGoogle Scholar
  57. 57.
    Carbunaru G, Prasad P, Scoccia B, Shea P, Hopwood N, Ziai F, Chang YT, Myers SE, Mason JI, Pang S. The hormonal phenotype of nonclassic 3 beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab 2004;89:783–94.PubMedCrossRefGoogle Scholar
  58. 58.
    Kahsar-Miller M, Boots LR, Bartolucci A, Azziz R. Role of a CYP17 polymorphism in the regulation of circulating dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome. Fertil Steril 2004;82:973–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Invitti C, Pecori Giraldi F, Dubini A, De Martin M, Cavagnini F. Increased urinary free cortisol and decreased serum corticosteroid-binding globulin in polycystic ovary syndrome. Acta Endocrinol (Copenh) 1991;125:28–32.Google Scholar
  60. 60.
    Prelevic GM, Wurzburger MI, Balint-Peric L. 24-hour serum cortisol profiles in women with polycystic ovary syndrome. Gynecol Endocrinol 1993;7:179–84.PubMedGoogle Scholar
  61. 61.
    Vogeser M, Halser B, Baron A, Jacob K, Demant T. Corticosteroid-binding globulin and unbound serum cortisol in women with polycystic ovary syndrome. Clin Biochem 2000;33:157–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Stewart PM, Penn R, Holder R, Parton A, Ratcliffe JG, London DR. The hypothalamo-pituitary-adrenal axis across the normal menstrual cycle and in polycystic ovary syndrome. Clin Endocrinol (Oxf) 1993;38:387–91.Google Scholar
  63. 63.
    Fassnacht M, Schlenz N, Schneider SB, Wudy SA, Allolio B, Arlt W. Beyond adrenal and ovarian androgen generation: increased peripheral 5 alpha-reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:2760–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Tsilchorozidou T, Honour JW, Conway GS. Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. J Clin Endocrinol Metab 2003;88:5907–13.PubMedCrossRefGoogle Scholar
  65. 65.
    Rodin A, Thakkar H, Taylor N, Clayton R. Hyperandrogenism in polycystic ovary syndrome. Evidence of dysregulation of 11 beta-hydroxysteroid dehydrogenase. N Engl J Med 1994;330:460–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Azziz R, Rittmaster RS, Fox LM, Bradley EL Jr, Potter HD, Boots LR.Role of the ovary in the adrenal androgen excess of hyperandrogenic women. Fertil Steril 1998;69:851–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Gonzalez F, Hatala DA, Speroff L. Adrenal and ovarian steroid hormone responses to gonadotropin-releasing hormone agonist treatment in polycystic ovary syndrome. Am J Obstet Gynecol 1991;165:535–45.PubMedGoogle Scholar
  68. 68.
    Rittmaster RS, Thompson DL. Effect of leuprolide and dexamethasone on hair growth and hormone levels in hirsute women: the relative importance of the ovary and the adrenal in the pathogenesis of hirsutism. J Clin Endocrinol Metab 1990;70:1096–102.PubMedCrossRefGoogle Scholar
  69. 69.
    Cedars MI, Steingold KA, de Ziegler D, Lapolt PS, Chang RJ, Judd HL. Long-term administration of gonadotropin-releasing hormone agonist and dexamethasone: assessment of the adrenal role in ovarian dysfunction. Fertil Steril 1992;57:495–500.PubMedGoogle Scholar
  70. 70.
    Slayden SM, Crabbe L, Bae S, Potter HD, Azziz R, Parker CR Jr. The effect of 17beta-estradiol on adrenocortical sensitivity, responsiveness, and steroidogenesis in postmenopausal women. J Clin Endocrinol Metab 1998;83:519–24.PubMedCrossRefGoogle Scholar
  71. 71.
    Chang WY, Stanczyk F, Bartolucci A, Azziz R. Effect of bilateral oophorectomy on basal and adrenocorticotropin (ACTH)-stimulated adrenal androgen (AA) secretion in polycystic ovary syndrome (PCOS). The 86th Annual Meeting of the Endocrine Society New Orleans, LA, 2004, June 16–19.Google Scholar
  72. 72.
    Azziz R, Zacur HA, Parker CR Jr, Bradley EL Jr, Boots LR. Effect of obesity on the response to acute adrenocorticotropin stimulation in eumenorrheic women. Fertil Steril 1991;56:427–33.PubMedGoogle Scholar
  73. 73.
    Farah-Eways LA, Reyna R, Knochenhauer ES, Bartolucci A, Azziz R. Glucose action and adrenocortical biosynthesis in the polycystic ovary syndrome. Fertil Steril 2004;81:120–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Azziz R, Fox LM, Zacur HA, Parker CR Jr, Boots LR. Adrenocortical secretion of dehydroepiandrosterone in healthy women: highly variable response to adrenocorticotropin. J Clin Endocrinol Metab 2001;86:2513–7.PubMedCrossRefGoogle Scholar

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© Humana Press 2008

Authors and Affiliations

  • Wendy Y. Chang
  • Ricardo Azziz

There are no affiliations available

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