In polycystic ovary syndrome (PCOS) the ovary produces markedly increased amounts of both androgens and estrogens in response to gonadotropin stimulation. Distinctive responses of 17-hydroxyprogesterone and androstenedione to ovarian stimulation testing suggest that ovarian hyperandrogenism is a result of dysregulation of theca cell androgen production which is intrinsic to the ovary. The occurrence of hyperestrogenism together with hyperandrogenism in PCOS suggests that whatever the abnormality of local regulatory factors of steroidogenesis, it affects granulosa as well as theca cells. Dysregulation is often associated with an increase in the number of follicles which evade atresia and reach the 2–8 mm stage of development. Autocrine/paracrine factors, especially those which are FSH-dependent, likely play an important role in the pathogenesis of the ovarian abnormality. Both LH and insulin hypersecretion probably play a secondary role in PCOS by amplifying the preexisting ovarian dysregulation. Because FSH secretion is under tight long-loop negative-feedback control and LH is not, hyperandrogenism is the primary clinical manifestation of dysregulation of steroid production in PCOS. However, anovulation in PCOS is most likely a result of excessive estrogen and inhibin production by multiple, small follicles which inhibit FSH secretory dynamics sufficiently to prevent selection of a dominant follicle.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Stein I.F., Leventhal M.L. Amenorrhea associated with bilateral polycystic ovaries. Am. J. Obstet. Gynecol. 29: 181, 1935.
Barnes R., Rosenfield R.L. The polycystic ovary syndrome: Pathogenesis and treatment. Ann. Intern. Med. 110: 386, 1989.
Barnes R.B., Rosenfield R.L., Burstein S., Ehrmann D.A. Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N. Engl. J. Med. 320: 559, 1989.
Rosenfield R.L., Barnes R.B., Ehrmann D.A. Studies of the nature of 17-hydroxyprogestrone hyperresponsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. J. Clin. Endocrinol. Metab. 79: 1686, 1994.
Sahin Y., Kelestimur F. 17-Hydroxyprogesterone response to buserelin testing in the polycystic ovary syndrome. Clin. Endocinol. 39: 151, 1993.
Ehrmann D.A., Barnes R.B., Rosenfield R.L. Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr. Rev. 16: 322, 1995.
Gilling-Smith C., Willis D.S., Beard R.W., Franks S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J. Clin. Endocrinol. Metab. 79: 1158, 1994.
Ehrmann D.A., Rosenfield R.L., Barnes R.B., Brigell D.F., Sheikh Z. Detection of functional ovarian hyperandrogenism in women with androgen excess. N. Engl. J. Med. 327: 157, 1992.
Rosenfield R.L., Barnes R.B., Cara J.F., Lucky A.W. Dysregulation of cytochrome P450c17α as the cause of polycystic ovarian syndrome. Fertil. Steril. 53: 785, 1990.
Barnes R.B., Ehrmann D.A., Brigell D.F., Rosenfield R.L. Ovarian steroidogenic responses to gonadotropin-releasing hormone agonist testing with nafarelin in hirsute women with adrenal responses to adrenocorticotropin suggestive of 3β-hydroxy-Δ5-steroid dehydrogenase deficiency. J. Clin. Endocrinol. Metab. 76: 450, 1993.
Azziz R., Bradley Jr E.L., Potter H.D., Boots L.R. Adrenal androgen excess in women: Lack of a role for 17-hydroxylase and 17,20-lyase dysregulation. J. Clin. Endocrinol. Metab. 80: 400, 1995.
Rosenfield R.L. Editorial: Evidence that idiopathic functional adrenal hyperandrogenism is caused by dysregulation of adrenal steroidogenesis and that hyperinsulinemia may be involved. J. Clin. Endocrinol. Metab. 81: 878, 1996.
Ibáñez L., Potau N., Virdis R., et al. Postpubertal outcome in girls diagnosed of premature pubarche during childhood: Increased frequency of functional ovarian hyderandrogenism. J. Clin. Endocrinol. Metab. 76: 1599, 1993.
Ibáñez L., Potau N., Zampolli M., Rique S., Saenger P., Carrascosa A. Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J. Clin. Endocrinol. Metab. 82: 2283, 1997.
Oppenheimer E., Under B., Dimartino-Nardi J. Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans. J. Clin. Endocrinol. Metab. 80: 614, 1995.
Apter D., Butzow T., Laughlin G.A., Yen S.S.C. 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. 79: 119, 1994.
Franks S. Polycystic ovary syndrome: A changing perspective. Clin. Endocrinol. 31: 87, 1989.
Clayton R.N., Ogden V., Hodgkinson J., et al. How common are polycystic ovaries in normal women and what is their significance for the fertility of the population? Clin. Endocrinol. 137: 127, 1992.
Franks S. Polycystic ovary syndrome. N. Engl. J. Med. 333: 853, 1995.
White D., Leigh A., Wilson C., Donaldson A., Franks S. Gonadotrophin and gonadal steroid response to a single dose of a long-acting agonist of gonadotrophin-releasing hormone in ovulatory and anovulatory women with polycystic ovary syndrome. Clin. Endocrinol. 42: 475, 1995.
Gilling-Smith C., Story H., Rogers V., Franks S. Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome. Clin. Endrocrinol. 47: 93, 1997.
Suikkari A.M., MacLachlan V., Montalto J., et al. Ultrasonographic appearance of polycystic ovaries is associated with exaggerated ovarian androgen and oestradial responses to gonadotrophin-releasing hormone agonist in women undergoing assisted reproduction treatment. Hum. Reprod. 10: 513, 1995.
Ibanez L., Hall J.E., Potau N., Carrascosa A., Prat N., Taylor A.E. 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. 81: 4103, 1996.
Barnes R.B. Diagnosis and therapy of hyperandrogenism. Baillieres Clin. Obstet. Gynaecol. 11: 369, 1997.
Messinis I.E., Milingos S.D. Current and future status of ovulation induction in polycystic ovary syndrome. Hum. Reprod. Update 3: 235, 1997.
Homburg R., Eschel A., Kilborn J., et al. Combined luteinizing hormone releasing hormone analogue and exogenous gonadotropins for the treatment of infertility associated with polycystic ovaries. Hum. Reprod. 5: 32, 1990.
Scheele F., Hompes P.G.A., Van der Meer M., et al. The effects of a gonadotrophin-releasing hormone agonist on treatment with low dose follicle stimulating hormone in polycystic ovary syndrome. Hum. Reprod. 8: 699, 1993.
Pigny P., Desailloud R., Cortet-Rudelli C., Duhamel A., Deroubaix-Allard D., Racadot A., Dewailly D. Serum α-inhibin levels in polycystic ovary syndrome: Relationship to the serum androstenedione level. J. Clin. Endocrinol. Metab. 82: 1939, 1997.
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.
Anderson R., Groome N., Baird D. Basal concentrations of inhibin B are higher in women with PCOS and show an abnormal pattern during monovulations in response to low-dose FSH. J. Endocrinol. 152 (Suppl.): P234, 1997 (abstract).
Barnes R.B. Pathophysiology of ovarian steroid secretion in polycystic ovary syndrome. Semin. Reprod. Endocrinol. 15: 159, 1997.
Barnes R.B., Wu E.F.S., Rosenfield R.L. Relative inhibition of 17,20-lyase activity by increasing doses of hCG in normal follicular phase women. Presented at the Society for Gynecologic Investigation, March 19–22, 1997, San Diego, CA.
Cheung A.P., Lu J.K.H., Chang R.J. Pulsatile gonadotrophin secretion in women with polycystic ovary syndrome after gonadotrophin-releasing hormone agonist treatment. Hum. Reprod. 12: 1156, 1997.
Rosenfield R.L. Current concepts of polycystic ovary syndrome. Balillieres Clin. Obstet. Gynaecol. 11: 307, 1997.
Levrant S.G., Barnes R.B., Rosenfield R.L. A pilot study of the human chorionic gonadotrophin test for ovarian hyperandrogenism. Hum. Reprod. 12: 1416, 1997.
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.
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.
Bames R.B., Rosenfield R.L., Ehrmann D.A., et al. Ovarian hyperandrogenism as a result of congenital adrenal virilizing disorders: Evidence for perinatal masculinization of neuroendocrine function in women. J. Clin. Endocrinol. Metab. 79: 1328, 1994.
Ghizzoni L., Virdis R., Vottero A., et al. Pituitary-ovarian responses to leuprolide acetate testing in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 81: 601, 1996.
McKenna T.J. Pathogenesis and treatment of polycystic ovary syndrome. N. Engl. J. Med. 318: 558, 1988.
Dunaif A., Graf M., Mandeli J., Lauma V., Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J. Clin. Endocrinol. Metabol. 65: 499, 1987.
Dunaif A., Segal K.R., Futterweit W., Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38: 1165, 1989.
Rajkhowa M., Bicknell J., Jones M., Clayton R.N. Insulin sensitivity in women with polycystic ovary syndrome: Relationship to hyperandrogenemia. Fertil. Steril. 61: 605, 1994.
Rittmaser R.S., Deshwal N., Lehman L. The role of adrenal hyperandrogenism, insulin resistance, and obesity in the pathogenesis of polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 76: 1295, 1993.
Chang R.J., Nakamura R.M., Judd H.L., Kaplan S.A. Insulin resistance in nonobese patients with polycystic ovarian disease. J. Clin. Endocrinol. Metab. 57: 356, 1983.
Jialal I., Naiker P., Reddi K., Moodley J., Joubert S.M. Evidence for insulin resistance in nonobese patients with polycystic ovarian disease. J. Clin. Endocrinol. Metab. 64: 1066, 1987.
Morales A.J., Laughlin G.A., Butzow Et, et al. 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.
Ovesen P., Moller J., Ingerslev H.J., et al. Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 77: 1636, 1993.
Holte J., Bergh T., Berne C., et al. Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J. Clin. Endocrinol. Metab. 78: 1052, 1994.
Dunaif A. Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis. Endocr. Rev. 18: 774, 1997.
Elkind-Hirsch K.E., Valdes C.T., McConnell T.G., Malinak L.R. Androgen responses to acutely increased endogenous insulin levels in hyperandrogenic and normal cycling women. Fertil. Steril. 55: 486, 1991.
Moghetti P., Castello R., Negri C., et al. Insulin infusion amplifies 17α-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: Apparent relative impairment of 17,20-lyase activity. J. Clin. Endocrinol. Metab. 81: 881, 1996.
Pasquali R., Antenucci D., Casimirri F., et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J. Clin. Endocrinol. Metab. 68: 173, 1989.
Kiddy D.S., Hamilton-Fairley D., Bush A., et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin. Endocrinol. 36: 105, 1992.
Wabitsch M., Hauner H., Heinze E., et al. Body fat distribution and steroid hormone concentration in obese adolescent girls before and after weight reduction. J. Clin. Endocrinol. Metab. 80: 3469, 1995.
Jakubowicz D.J., Nestler J.E. 17α-Hydroxyprogesterone responds to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome after dietary weight loss. J. Clin. Endocrinol. Metab. 82: 556, 1997.
Holte J., Bergh T., Berne, et al. Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 80: 2586, 1995.
Nestler J.E., Barlascini C.O., Matt D.W., et al. Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J. Clin. Endocrin. Metab. 68: 1027, 1989.
Prelevic G.M., Wurzburger M.I., Balint-Peric L., Nesic J.S. Inhibitory effect of sandostatin on secretion of luteinising hormone and ovarian steroids in polycystic ovary syndrome. Lancet 336: 900, 1990.
Dunaif A., Scott D., Finegood D., et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 81: 3299, 1996.
Ehrmann D.A., Schneider D.J., Sobel B.E., Cavaghan M.K., Imperial J., Rosenfield R.L., Polonsky K.S. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 82: 2108, 1997.
Nestler J.E., Jakubowicz D.J. Decreases in ovarian cytochrome P450c17 activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N. Engl. J. Med. 335: 617, 1996.
Nestler J.E., Jakubowicz D.J. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17α activity and serum androgens. J. Clin. Endocrinol. Metab. 82: 4075, 1997.
Ehrmann D.A., Cavaghan M.K., Imperial J., Stuns J., Rosenfield R.L., Polonsky K.S. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 82: 524, 1997.
Fulghesu A.M., Villa P., Pavone V., Guido M., Apa R., Caruso A., Lanzone A., Rossodivita A., Mancuso S. The impact of insulin secretion on the the ovarian response to exogenous gonadotropins in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 82: 644, 1997.
Zhang L.H., Rodriguez H., Ohno S., Miller W.L. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: Implications for adrenarche and the polycystic ovary syndrome. Proc. Natl. Acad. Sci. USA 92: 10619, 1995.
Dunaif A., Xia J., Brook C.B., et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. J. Clin. Invest. 96: 801, 1995.
Bjorntorp P. The android women-a risky condition. J. Intern. Med. 239: 105, 1996.
Speiser P.W., Serrat J., New M.I., Gertner J.M. Insulin insensitivity in adrenal hyperplasia due to non-classical steroid 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 75: 1421, 1992.
Gharani N., Waterworth D.M., Williamson R., Franks S. 5′ polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries. J. Clin. Endocrinol. Metab. 81: 4174, 1996.
Giudice L.C., Cataldo N.A., van Dessel T., et al. Growth factors in normal ovarian follicle development. Seminars Reprod. Endocrinol. 14: 179, 1996.
Giudice L.C., Morales A.J., Yen S.S.C. Growth factors and polycystic ovarian syndrome. Semin. Reprod. Endocrinol. 14: 203, 1996.
Klinger B., Anin S., Silbergeld A., Eshet R., Laron Z. Development of hyperandrogenism during treatment with insulin-like growth factor-I (IGF-I) in female patients with Laron syndrome. Clin. Endocrinol. 48: 81, 1998.
Rabin D., Spitz I., Bergovici B., et al. Isolated deficiency of follicle-stimulating hormone. N. Eng. J. Med. 287: 1313, 1972.
Matthews C.H., Borgato S., Peccoz B., et al. Primary amenorrhoea and infertility due to a mutation in the β-subunit of follicle-stimulating hormone. Nat. Genet. 5: 83, 1993.
Layman L.C., Lee E.J., Peak D.B., Namnoum A.B., Vu K.V., van Ungen B.L., Gray M.R., McDonough P.G., Reindollar R.H., Jameson J.L. Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone β-subunit gene. N. Eng. J. Med. 337: 607, 1997.
Magarelli P., Zachow R., Magoffin D. Developmental and hormonal regulation of rat theca-cell differentiation factor secretion in ovarian follicles. Biol. Reprod. 55: 416, 1996.
Smyth C., Miro F., Whitelaw P., Howies C., Hillier S. Ovarian thecal/interstitial androgen synthesis is enhanced by a follicle-stimulating hormone-stimulated paracrine mechanism. Endocrinology 133: 1532, 1993.
Hsueh A.J.W., Dahl K.D., 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 84: 5082, 1987.
Henderson K., Franchimont P. Inhibin production by bovine ovarian tissues in vitro and its regulation by androgens. J. Reprod. Fert. 67: 291, 1983.
Hillier S., Wickings E., Illingworth P., et al. Control of inhibin production by human granulosa cells. Clin. Endocrinol. 35: 71, 1991.
Hillier S., Yong E., Illingworth P., Baird D., Schwall R., Mason A. Effect of recombinant activin on androgen synthesis in cultured human thecal cells. J. Clin. Endocrinol. Metab. 1206, 1991.
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. 83: 99, 1998.
Hsueh A.J., Billig H., Tsafrir A. Ovarian follicle atresia: A hormonally controlled apoptotic process. Endocr. Rev. 15: 707, 1994.
Pache T.D., Hop W.C.J., de Jong F.H., Leerentveld R.A., van Deldorp H., Van de Kamp T.M.M., Gooren L.J.G., Fauser B.C.J.M. 17β-oestradiol, androstenedione and inhibin levels in fluid from individual follicles of normal and polycystic ovaries and in ovaries from androgen treated female to male transsexuals. Clin. Endocrinol. 36: 565, 1992.
Mason H.D., Willis D.S., Beard R.W., Winston R.M.L., Margara R., Franks S. Estradiol production by granulosa cells of normal and polycystic ovaries: Relationship to menstrual cycle history and concentrations of gonadotropins and sex steroids in follicular fluid. J. Clin. Endocrinol. Metab. 79: 1355, 1994.
Hild-Petito S., West N.B., Brenner R.M., Stouffer R.L. Localization of androgen receptor in the follicle and corpus luteum of the primate ovary during the menstrual cycle. Biol. Reprod. 44: 561, 1991.
Hillier S.G., Tetsuka A. Role of androgens in follicle maturation and atresia. Baillieres Clin. Obstet. Gynaecol. 11: 249, 1997.
Gougeon A. Regulation of ovarian follicular development in primates: Facts and hypothesis. Endocr. Rev. 17: 121, 1996.
Haning Jr. R.V., Hackett R.J., Flood C.A., Loughlin J.S., Zhao Q.Y., Longcope C. Testosterone, a follicular regulator: Key to anovulation. J. Clin. Endocrinol. Metab. 77: 710, 1993.
Willis D., Mason H., Gilling-Smith C., Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J. Clin. Endocrinol. Metab. 81: 302, 1996.
Vendola K.A., Zhou J., Adesanya O.O., Weil S.J., Bondy C.A. Testosterone promotes primate follicular growth and survival. Presented at the Endocrine Society, June 24–27, 1998, New Orleans LA.
Spearow J.L. Regulation of ovulation rate. In Chang R.J. (Ed.), Polycystic Ovary Syndrome. Springer-Verlag, New York, 1996, pp. 1–20.
Wada I., Matson P.L., Macnamee M.C., Brinsden P.R., Lieberman B.A. High ovarian response in Yoruba African women during ovulation inductin for assisted conception. Hum. Reprod. 9: 1077, 1994.
About this article
Cite this article
Barnes, R.B. The pathogenesis of polycystic ovary syndrome: Lessons from ovarian stimulation studies. J Endocrinol Invest 21, 567–579 (1998). https://doi.org/10.1007/BF03350782
- Polycystic ovary syndrome
- functional ovarian hyperandrogenism
- theca cell
- granulosa cell