Advertisement

PCOS: an ovarian disorder that leads to dysregulation in the hypothalamic–pituitary–adrenal axis?

      Abstract

      This review focuses on the role of the ovaries in the pathogenesis of the polycystic ovarian syndrome. In particular, the failure of follicular development, hypothalamo-pituitary dysregulation, alterations in adrenal steroid output and derangement of intermediary metabolism are discussed in the context of the ovaries. It is concluded that the central and adrenal alterations associated with PCOS are unlikely to be primary but rather are secondary to the events within the ovary.

      Abbreviations:

      Δ4 pathway (the steroid pathway from P4-17POA4), Δ5 pathway (the steroid pathway from P5-17PE-DHEA), 3βHSD (3β-hydroxysteroid dehydrogenase), 17βHSD (17β-hydroxysteroid dehydrogenase), 17PE (17α-hydroxypregnenolone), 17PO (17α-hydroxyprogesterone), A4 (androstenedione), ACTH (adrenocorticotrophic hormone), DHEA (dehydroepiandrosterone), DHEAS (dehydroepiandrosterone sulphate), E2 (estradiol), FSH (follicle stimulating hormone), GnRH (gonadotrophin releasing hormone), hCG (human chorionic gonadotrophin), IGF-1 (insulin like growth factor 1), LH (luteinising hormone), P4 (progesterone), P450c17 (microsomal enzyme that has both 17α-hydroxylase and 17,20-lyase activities), P5 (pregnenolone), PCOS (polycystic ovary syndrome), T (testosterone)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • Franks S.
        Adult polycystic ovary syndrome begins in childhood.
        Best Pract Res Clin Endocrinol Metab. 2002; 16: 263-272
        • Fox R.
        • Ryan A.
        Polycystic ovary syndrome: not ovarian, not simple, unkind.
        Hum Fertil (Camb). 2002; 5: S28-S32
        • Barnes R.
        • Rosenfield R.L.
        The polycystic ovary syndrome: pathogenesis and treatment.
        Ann Intern Med. 1989; 110: 386-399
        • 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. 1989; 320: 559-565
        • Rosenfield R.L.
        Current concepts of polycystic ovary syndrome.
        Baillieres Clin Obstet Gynaecol. 1997; 11: 307-333
        • 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. 1992; 327: 157-162
        • Carmina E.
        • Lobo R.A.
        Do hyperandrogenic women with normal menses have polycystic ovary syndrome?.
        Fertil Steril. 1999; 71: 319-322
        • Carmina E.
        • Wong L.
        • Chang L.
        • et al.
        Endocrine abnormalities in ovulatory women with polycystic ovaries on ultrasound.
        Hum Reprod. 1997; 12: 905-909
        • Chang P.L.
        • Lindheim S.R.
        • Lowre C.
        • et al.
        Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary–ovarian responses to gonadotropin-releasing hormone-agonist testing.
        J Clin Endocrinol Metab. 2000; 85: 995-1000
        • Legro R.S.
        • Driscoll D.
        • Strauss 3rd, J.F.
        • Fox J.
        • Dunaif A.
        Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome.
        Proc Natl Acad Sci USA. 1998; 95: 14956-14960
      1. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.
        Fertil Steril. 2004; 81: 19-25
        • Kirschner M.A.
        • Zucker I.R.
        • Jespersen D.
        Idiopathic hirsutism—an ovarian abnormality.
        N Engl J Med. 1976; 294: 637-640
        • Barontini M.
        • Garcia-Rudaz M.C.
        • Veldhuis J.D.
        Mechanisms of hypothalamic–pituitary–gonadal disruption in polycystic ovarian syndrome.
        Arch Med Res. 2001; 32: 544-552
        • Pache T.D.
        • Hop W.C.
        • de Jong F.H.
        • et al.
        17beta-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 (Oxf). 1992; 36: 565-571
        • Anderson R.A.
        • Groome N.P.
        • Baird D.T.
        Inhibin A and inhibin B in women with polycystic ovarian syndrome during treatment with FSH to induce mono-ovulation.
        Clin Endocrinol (Oxf). 1998; 48: 577-584
        • Baird D.T.
        • Corker C.S.
        • Davidson D.W.
        • et al.
        Pituitary–ovarian relationships in polycystic ovary syndrome.
        J Clin Endocrinol Metab. 1977; 45: 798-801
        • Seibel M.M.
        • Kamrava M.M.
        • McArdle C.
        • Taymor M.L.
        Treatment of polycystic ovary disease with chronic low-dose follicle stimulating hormone: biochemical changes and ultrasound correlation.
        Int J Fertil. 1984; 29: 39-43
        • Shoham Z.
        • Patel A.
        • Jacobs H.S.
        Polycystic ovarian syndrome: safety and effectiveness of stepwise and low-dose administration of purified follicle-stimulating hormone.
        Fertil Steril. 1991; 55: 1051-1056
        • Hamilton-Fairley D.
        • Kiddy D.
        • Watson H.
        • Sagle M.
        • Franks S.
        Low-dose gonadotrophin therapy for induction of ovulation in 100 women with polycystic ovary syndrome.
        Hum Reprod. 1991; 6: 1095-1099
        • Klein N.A.
        • Illingworth P.J.
        • Groome N.P.
        • et al.
        Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles.
        J Clin Endocrinol Metab. 1996; 81: 2742-2745
        • Welt C.K.
        • McNicholl D.J.
        • Taylor A.E.
        • Hall J.E.
        Female reproductive aging is marked by decreased secretion of dimeric inhibin.
        J Clin Endocrinol Metab. 1999; 84: 105-111
        • Danforth D.R.
        • Arbogast L.K.
        • Mroueh J.
        • et al.
        Dimeric inhibin: a direct marker of ovarian aging.
        Fertil Steril. 1998; 70: 119-123
        • Goudas V.T.
        • Dumesic D.A.
        Polycystic ovary syndrome.
        Endocrinol Metab Clin North Am. 1997; 26: 893-912
        • Buckler H.M.
        • McLachlan R.I.
        • MacLachlan V.B.
        • Healy D.L.
        • Burger H.G.
        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. 1988; 66: 798-803
        • Robertson D.
        • Burger H.G.
        • Sullivan J.
        • et al.
        Biological and immunological characterization of inhibin forms in human plasma.
        J Clin Endocrinol Metab. 1996; 81: 669-676
        • Robertson D.M.
        • Sullivan J.
        • Watson M.
        • Cahir N.
        Inhibin forms in human plasma.
        J Endocrinol. 1995; 144: 261-269
        • Norman R.J.
        • Milner C.R.
        • Groome N.P.
        • Robertson D.M.
        Circulating follistatin concentrations are higher and activin concentrations are lower in polycystic ovarian syndrome.
        Hum Reprod. 2001; 16: 668-672
        • Pigny P.
        • Cortet-Rudelli C.
        • Decanter C.
        • et al.
        Serum levels of inhibins are differentially altered in patients with polycystic ovary syndrome: effects of being overweight and relevance to hyperandrogenism.
        Fertil Steril. 2000; 73: 972-977
        • Laven J.S.
        • Imani B.
        • Eijkemans M.J.
        • de Jong F.H.
        • Fauser B.C.
        Absent biologically relevant associations between serum inhibin B concentrations and characteristics of polycystic ovary syndrome in normogonadotrophic anovulatory infertility.
        Hum Reprod. 2001; 16: 1359-1364
        • Cortet-Rudelli C.
        • Pigny P.
        • Decanter C.
        • et al.
        Obesity and serum luteinizing hormone level have an independent and opposite effect on the serum inhibin B level in patients with polycystic ovary syndrome.
        Fertil Steril. 2002; 77: 281-287
        • Elting M.W.
        • Kwee J.
        • Schats R.
        • Rekers-Mombarg L.T.
        • Schoemaker J.
        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: 1589-1595
        • Muttukrishna S.
        • Knight P.G.
        Inverse effects of activin and inhibin on the synthesis and secretion of FSH and LH by ovine pituitary cells in vitro.
        J Mol Endocrinol. 1991; 6: 171-178
        • Dahl K.D.
        • Campen C.A.
        • McGuinness D.M.
        • Vale W.
        Differential regulation in the release of bioactive versus immunoactive gonadotropins from cultured rat pituitary cells by inhibin and androgens.
        J Androl. 1992; 13: 526-533
        • Hayes F.J.
        • Pitteloud N.
        • DeCruz S.
        • Crowley Jr., W.F.
        • Boepple P.A.
        Importance of inhibin B in the regulation of FSH secretion in the human male.
        J Clin Endocrinol Metab. 2001; 86: 5541-5546
        • Conte F.A.
        • Grumbach M.M.
        • Ito Y.
        • Fisher C.R.
        • Simpson E.R.
        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: 1287-1292
        • Di Cerbo A.
        • Biason-Lauber A.
        • Savino M.
        • et al.
        Combined 17alpha-Hydroxylase/17,20-lyase deficiency caused by Phe93Cys mutation in the CYP17 gene.
        J Clin Endocrinol Metab. 2002; 87: 898-905
        • Meirow D.
        • Schenker J.G.
        • Rosler A.
        Ovarian hyperstimulation syndrome with low oestradiol in non-classical 17-alpha-hydroxylase, 17,20-lyase deficiency: what is the role of oestrogens?.
        Hum Reprod. 1996; 11: 2119-2121
        • Fisher S.A.
        • Reid R.L.
        • Van Vugt D.A.
        • Casper R.F.
        A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women.
        Fertil Steril. 2002; 78: 280-285
        • Mitwally M.F.
        • Casper R.F.
        Aromatase inhibition for ovarian stimulation: future avenues for infertility management.
        Curr Opin Obstet Gynecol. 2002; 14: 255-263
        • Mitwally M.F.
        • Casper R.F.
        Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.
        Fertil Steril. 2001; 75: 305-309
        • Ali Hassan H.
        • El-Gezeiry D.
        • Nafaa T.M.
        • Baghdady I.
        Improved responsiveness of PCOS patients to clomiphene after CYP17a inhibitor.
        J Assist Reprod Genet. 2001; 18: 608-611
        • 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. 1994; 79: 1158-1165
        • Ibanez L.
        • Hall J.E.
        • Potau N.
        • et al.
        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: 4103-4107
        • Levrant S.G.
        • Barnes R.B.
        • Rosenfield R.L.
        A pilot study of the human chorionic gonadotrophin test for ovarian hyperandrogenism.
        Hum Reprod. 1997; 12: 1416-1420
        • 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: 93-99
        • McCartney C.R.
        • Bellows A.B.
        • Gingrich M.B.
        Exaggerated 17-hydroxyprogesterone response to intravenous infusions of recombinant human LH in women with polycystic ovary syndrome.
        Am J Physiol Endocrinol Metab. 2004; 286 (Epub 2004, Jan 21): E902-E908
        • 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. 1995; 16: 322-353
        • Morishima A.
        • Grumbach M.M.
        • Simpson E.R.
        • Fisher C.
        • Qin K.
        Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens.
        J Clin Endocrinol Metab. 1995; 80: 3689-3698
        • Layman L.C.
        • Lee E.J.
        • Peak D.B.
        • et al.
        Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone beta-subunit gene.
        N Engl J Med. 1997; 337: 607-611
        • Rabin D.
        • Spitz I.
        • Bercovici B.
        • et al.
        Isolated deficiency of follicle-stimulating hormone. Clinical and laboratory features.
        N Engl J Med. 1972; 287: 1313-1317
        • Matthews C.H.
        • Borgato S.
        • Beck-Peccoz P.
        • et al.
        Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone.
        Nat Genet. 1993; 5: 83-86
        • Barnes R.B.
        • Namnoum A.B.
        • Rosenfield R.L.
        • Layman L.C.
        The role of LH and FSH in ovarian androgen secretion and ovarian follicular development: clinical studies in a patient with isolated FSH deficiency and multicystic ovaries.
        Hum Reprod. 2002; 17: 88-91
        • Coffler M.S.
        • Patel K.
        • Dahan M.H.
        • et al.
        Evidence for abnormal granulosa cell responsiveness to follicle-stimulating hormone in women with polycystic ovary syndrome.
        J Clin Endocrinol Metab. 2003; 88: 1742-1747
        • Marshall J.C.
        • Eagleson C.A.
        • McCartney C.R.
        Hypothalamic dysfunction.
        Mol Cell Endocrinol. 2001; 183: 29-32
        • Kirk S.E.
        • Dalkin A.C.
        • Yasin M.
        • Haisenleder D.J.
        • Marshall J.C.
        Gonadotropin-releasing hormone pulse frequency regulates expression of pituitary follistatin messenger ribonucleic acid: a mechanism for differential gonadotrope function.
        Endocrinology. 1994; 135: 876-880
        • Miller W.L.
        • Shafiee-Kermani F.
        • Strahl B.D.
        • Huang H.J.
        The nature of FSH induction by GnRH.
        Trends Endocrinol Metab. 2002; 13: 257-263
        • Eldar-Geva T.
        • Spitz I.M.
        • Groome N.P.
        • Margalioth E.J.
        • Homburg R.
        Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome.
        Hum Reprod. 2001; 16: 2552-2556
        • Hayes F.J.
        • Taylor A.E.
        • Martin K.A.
        • Hall J.E.
        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: 2343-2349
        • 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. 1998; 83: 582-590
        • Eagleson C.A.
        • Gingrich M.B.
        • Pastor C.L.
        • 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: 4047-4052
        • Patel K.
        • Coffler M.S.
        • Dahan M.H.
        • et al.
        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
        • Buffet N.C.
        • Bouchard P.
        The neuroendocrine regulation of the human ovarian cycle.
        Chronobiol Int. 2001; 18: 893-919
        • McConnell D.S.
        • Wang Q.
        • Sluss P.M.
        • et al.
        A two-site chemiluminescent assay for activin-free follistatin reveals that most follistatin circulating in men and normal cycling women is in an activin-bound state.
        J Clin Endocrinol Metab. 1998; 83: 851-858
        • Escobar-Morreale H.F.
        • Asuncion M.
        • Calvo R.M.
        • Sancho J.
        • San Millan J.L.
        Receiver operating characteristic analysis of the performance of basal serum hormone profiles for the diagnosis of polycystic ovary syndrome in epidemiological studies.
        Eur J Endocrinol. 2001; 145: 619-624
        • Vanky E.
        • Salvesen K.A.
        • Carlsen S.M.
        Six-month treatment with low-dose dexamethasone further reduces androgen levels in PCOS women treated with diet and lifestyle advice, and metformin.
        Hum Reprod. 2004; 19: 529-533
        • Couzinet B.
        • Meduri G.
        • Lecce M.G.
        • et al.
        The postmenopausal ovary is not a major androgen-producing gland.
        J Clin Endocrinol Metab. 2001; 86: 5060-5066
        • Gebre-Medhin G.
        • Husebye E.S.
        • Mallmin H.
        • et al.
        Oral dehydroepiandrosterone (DHEA) replacement therapy in women with Addison's disease.
        Clin Endocrinol (Oxf). 2000; 52: 775-780
        • Piltonen T.
        • Koivunen R.
        • Morin-Papunen L.
        • et al.
        Ovarian and adrenal steroid production: regulatory role of LH/HCG.
        Hum Reprod. 2002; 17: 620-624
        • Bermudez J.A.
        • Moran C.
        • Herrera J.
        • et al.
        Determination of the steroidogenic capacity in premature ovarian failure.
        Fertil Steril. 1993; 60: 668-671
        • De Geyter C.
        • De Geyter M.
        • Huber P.R.
        • Nieschlag E.
        • Holzgreve W.
        Progesterone serum levels during the follicular phase of the menstrual cycle originate from the crosstalk between the ovaries and the adrenal cortex.
        Hum Reprod. 2002; 17: 933-939
        • Judd H.L.
        • Lucas W.E.
        • Yen S.S.
        Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer.
        Am J Obstet Gynecol. 1974; 118: 793-798
        • Reame N.E.
        • Kelche R.P.
        • Beitins I.Z.
        • et al.
        Age effects of follicle-stimulating hormone and pulsatile luteinizing hormone secretion across the menstrual cycle of premenopausal women.
        J Clin Endocrinol Metab. 1996; 81: 1512-1518
        • Santoro N.
        • Banwell T.
        • Tortoriello D.
        • et al.
        Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women.
        Am J Obstet Gynecol. 1998; 178: 732-741
        • Muttukrishna S.
        • Sharma S.
        • Barlow D.H.
        • et al.
        Serum inhibins, estradiol, progesterone and FSH in surgical menopause: a demonstration of ovarian pituitary feedback loop in women.
        Hum Reprod. 2002; 17: 2535-2539
        • Cheung A.P.
        • Pride S.M.
        • Yuen B.H.
        • Sy L.
        In-vivo ovarian androgen responses to recombinant FSH with and without recombinant LH in polycystic ovarian syndrome.
        Hum Reprod. 2002; 17: 2540-2547
        • Hsueh A.J.
        • 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. 1987; 84: 5082-5086
        • Smyth C.D.
        • Miro F.
        • Whitelaw P.F.
        • Howles C.M.
        • Hillier S.G.
        Ovarian thecal/interstitial androgen synthesis is enhanced by a follicle-stimulating hormone-stimulated paracrine mechanism.
        Endocrinology. 1993; 133: 1532-1538
        • Barnes R.B.
        • Rosenfield R.L.
        • Namnoum A.
        • Layman L.C.
        Effect of follicle-stimulating hormone on ovarian androgen production in a woman with isolated follicle-stimulating hormone deficiency.
        N Engl J Med. 2000; 343: 1197-1198
        • Parsanezhad M.E.
        • Bagheri M.H.
        • Alborzi S.
        • Schmidt E.H.
        Ovarian stromal blood flow changes after laparoscopic ovarian cauterization in women with polycystic ovary syndrome.
        Hum Reprod. 2003; 18: 1432-1437
        • Carmina E.
        • Longo A.
        • Lobo R.A.
        Does ovarian blood flow distinguish between ovulatory and anovulatory patients with polycystic ovary syndrome?.
        Am J Obstet Gynecol. 2003; 189: 1283-1286
        • Wu X.K.
        • Zhou S.Y.
        • Sallinen K.
        • Pollanen P.
        • Erkkola R.
        Ovarian–adrenal cross-talk in polycystic ovary syndrome: evidence from wedge resection.
        Eur J Endocrinol. 2000; 143: 383-388
        • Khamsi F.
        • Roberge S.
        • Yavas Y.
        • et al.
        Recent discoveries in physiology of insulin-like growth factor-1 and its interaction with gonadotropins in folliculogenesis.
        Endocrine. 2001; 16: 151-165
        • Cara J.F.
        • Fan J.
        • Azzarello J.
        • Rosenfield R.L.
        Insulin-like growth factor-I enhances luteinizing hormone binding to rat ovarian theca-interstitial cells.
        J Clin Invest. 1990; 86: 560-565
        • Dunaif A.
        • Green G.
        • Phelps R.G.
        • et al.
        Acanthosis Nigricans, insulin action, and hyperandrogenism: clinical, histological, and biochemical findings.
        J Clin Endocrinol Metab. 1991; 73: 590-595
        • Legro R.S.
        • Castracane V.D.
        • Kauffman R.P.
        Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls.
        Obstet Gynecol Surv. 2004; 59: 141-154
        • 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: 241-249
        • Sattar N.
        • Hopkinson Z.E.
        • Greer I.A.
        Insulin-sensitising agents in polycystic ovary syndrome.
        Lancet. 1998; 351: 305-307
        • Seli E.
        • Duleba A.J.
        Should patients with polycystic ovarian syndrome be treated with metformin?.
        Hum Reprod. 2002; 17: 2230-2236
        • Loverro G.
        • Lorusso F.
        • De Pergola G.
        • et al.
        Clinical and endocrinological effects of 6 months of metformin treatment in young hyperinsulinemic patients affected by polycystic ovary syndrome.
        Gynecol Endocrinol. 2002; 16: 217-224
        • Ehrmann D.A.
        • Schneider D.J.
        • Sobel B.E.
        • 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: 2108-2116
        • Hasegawa I.
        • Murakawa H.
        • Suzuki M.
        • et al.
        Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome.
        Fertil Steril. 1999; 71: 323-327
        • Geffner M.E.
        • Kaplan S.A.
        • Bersch N.
        • et al.
        Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion.
        Fertil Steril. 1986; 45: 327-333
        • Singer F.
        • Bhargava G.
        • Poretsky L.
        Persistent insulin resistance after normalization of androgen levels in a woman with congenital adrenal hyperplasia. A case report.
        J Reprod Med. 1989; 34: 921-922
        • Azziz R.
        • Deal C.L.
        • Potter H.D.
        • Gargosky S.E.
        • Rosenfeld R.G.
        Regulation of extragonadal insulin-like growth factor-binding protein-3 by testosterone in oophorectomized women.
        J Clin Endocrinol Metab. 1994; 79: 1747-1751
        • 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 Endocrinol Metab. 1989; 68: 1027-1032
        • Dunaif A.
        • Scott D.
        • Finegood D.
        • Quintana B.
        • Whitcomb R.
        The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome.
        J Clin Endocrinol Metab. 1996; 81: 3299-3306
        • Li M.
        • Youngren J.F.
        • Dunaif A.
        • et al.
        Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators.
        J Clin Endocrinol Metab. 2002; 87: 4088-4093
        • Dunaif A.
        Insulin action in the polycystic ovary syndrome.
        Endocrinol Metab Clin North Am. 1999; 28: 341-359
        • Legro R.S.
        Insulin resistance in polycystic ovary syndrome: treating a phenotype without a genotype.
        Mol Cell Endocrinol. 1998; 145: 103-110
        • Nestler J.E.
        • Powers L.P.
        • Matt D.W.
        • et al.
        A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome.
        J Clin Endocrinol Metab. 1991; 72: 83-89
        • Rheinwald J.G.
        • Green H.
        Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes.
        Nature. 1977; 265: 421-424
        • Diamond M.P.
        • Grainger D.A.
        • Laudano A.J.
        • Starick-Zych K.
        • DeFronzo R.A.
        Effect of acute physiological elevations of insulin on circulating androgen levels in nonobese women.
        J Clin Endocrinol Metab. 1991; 72: 883-887
        • Nestler J.E.
        • Clore J.N.
        • Strauss 3rd, J.F.
        • Blackard W.G.
        The effects of hyperinsulinemia on serum testosterone, progesterone, dehydroepiandrosterone sulfate, and cortisol levels in normal women and in a woman with hyperandrogenism, insulin resistance, and acanthosis nigricans.
        J Clin Endocrinol Metab. 1987; 64: 180-184
        • Poretsky L.
        On the paradox of insulin-induced hyperandrogenism in insulin-resistant states.
        Endocr Rev. 1991; 12: 3-13
        • Barbieri R.L.
        • Makris A.
        • Ryan K.J.
        Effects of insulin on steroidogenesis in cultured porcine ovarian theca.
        Fertil Steril. 1983; 40: 237-241
        • Wu X.K.
        • Zhou S.Y.
        • Liu J.X.
        • et al.
        Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome.
        Fertil Steril. 2003; 80: 954-965
        • Hillier S.G.
        Gonadotropic control of ovarian follicular growth and development.
        Mol Cell Endocrinol. 2001; 179: 39-46
        • Pao C.I.
        • Farmer P.K.
        • Begovic S.
        • et al.
        Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding protein 1 gene transcription by hormones and provision of amino acids in rat hepatocytes.
        Mol Endocrinol. 1993; 7: 1561-1568
        • Poretsky L.
        • Glover B.
        • Laumas V.
        • Kalin M.
        • Dunaif A.
        The effects of experimental hyperinsulinemia on steroid secretion, ovarian.
        Endocrinology. 1988; 122: 581-585
        • De Leo V.
        • La Marca A.
        • Orvieto R.
        • Morgante G.
        Effect of metformin on insulin-like growth factor (IGF) I and IGF- binding protein I in polycystic ovary syndrome.
        J Clin Endocrinol Metab. 2000; 85: 1598-1600
        • Hillier S.G.
        • Yong E.L.
        • Illingworth P.J.
        • et al.
        Effect of recombinant inhibin on androgen synthesis in cultured human thecal cells.
        Mol Cell Endocrinol. 1991; 75: R1-R6
        • Welt C.K.
        • Schneyer A.L.
        Differential regulation of inhibin B and inhibin a by follicle- stimulating hormone and local growth factors in human granulosa cells from small antral follicles.
        J Clin Endocrinol Metab. 2001; 86: 330-336
        • Giudice L.C.
        Insulin-like growth factors and ovarian follicular development.
        Endocr Rev. 1992; 13: 641-669
        • el-Roeiy A.
        • Chen X.
        • Roberts V.J.
        • et al.
        Expression of insulin-like growth factor-I (IGF-I) and IGF-II and the IGF-I, IGF-II, and insulin receptor genes and localization of the gene products in the human ovary.
        J Clin Endocrinol Metab. 1993; 77: 1411-1418
        • Silfen M.E.
        • Manibo A.M.
        • Ferin M.
        • et al.
        Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity.
        J Clin Endocrinol Metab. 2002; 87: 398-403
        • Homburg R.
        • Pariente C.
        • Lunenfeld B.
        • Jacobs H.S.
        The role of insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) in the pathogenesis of polycystic ovary syndrome.
        Hum Reprod. 1992; 7: 1379-1383
        • Tiitinen A.E.
        • Laatikainen T.J.
        • Seppala M.T.
        Serum levels of insulin-like growth factor binding protein-1 and ovulatory responses to clomiphene citrate in women with polycystic ovarian disease.
        Fertil Steril. 1993; 60: 58-62
        • Morales A.J.
        • Laughlin G.A.
        • Butzow T.
        • 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. 1996; 81: 2854-2864
        • Giudice L.C.
        Growth factor action on ovarian function in polycystic ovary syndrome.
        Endocrinol Metab Clin North Am. 1999; 28 (vi): 325-339
        • Nelson V.L.
        • Qin Kn K.N.
        • Rosenfield R.L.
        • et al.
        The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome.
        J Clin Endocrinol Metab. 2001; 86: 5925-5933
        • Carbunaru G.
        • Prasad P.
        • Scoccia B.
        • et al.
        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: 783-794
        • Fluck C.E.
        • Miller W.L.
        • Auchus R.J.
        The 17,20-lyase activity of cytochrome p450c17 from human fetal testis favors the delta5 steroidogenic pathway.
        J Clin Endocrinol Metab. 2003; 88: 3762-3766
        • Swart A.C.
        • Kolar N.W.
        • Lombard N.
        • Mason J.I.
        • Swart P.
        Baboon cytochrome P45017alpha-hydroxylase/17,20-lyase (CYP17).
        Eur J Biochem. 2002; 269: 5608-5616
        • Remsberg K.
        • Talbott E.
        • Zborowski J.
        • Evans R.
        • McHugh-Pemu K.
        Evidence for competing effects of body mass, hyperinsulinemia, insulin resistance, and androgens on leptin levels among lean, overweight, and obese women with polycystic ovary syndrome.
        Fertil Steril. 2002; 78: 479
        • Arroyo A.
        • Laughlin G.A.
        • Morales A.J.
        • Yen S.S.
        Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity.
        J Clin Endocrinol Metab. 1997; 82: 3728-3733
        • Grulet H.
        • Hecart A.C.
        • Delemer B.
        • et al.
        Roles of LH and insulin resistance in lean and obese polycystic ovary syndrome.
        Clin Endocrinol (Oxf). 1993; 38: 621-626
        • Dale P.O.
        • 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: 487-491
        • Ke W.X.
        • Shan G.Q.
        • Hua S.Y.
        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: 166-169
        • Banaszewska B.
        • Spaczynski R.Z.
        • 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: 131-134
        • Toprak S.
        • Yonem A.
        • Cakir B.
        • et al.
        Insulin resistance in nonobese patients with polycystic ovary syndrome.
        Horm Res. 2001; 55: 65-70
        • Tropeano G.
        • Vuolo I.P.
        • 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: 139-145
        • Jakubowicz D.J.
        • Nestler J.E.
        17 alpha-Hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome offer dietary weight loss.
        J Clin Endocrinol Metab. 1997; 82: 556-560
        • Comim F.V.
        • Spritzer P.M.
        Increased growth hormone response to clonidine in nonobese normoinsulinemic patients with polycystic ovary syndrome.
        Fertil Steril. 2004; 81: 108-113
        • Hashimoto S.
        • Yatabe J.
        • Midorikawa S.
        • Sanada H.
        • Watanabe T.
        Inhibition of growth hormone excess reduces insulin resistance and ovarian dysfunction in a lean case of polycystic ovary syndrome with a growth-hormone-producing pituitary adenoma.
        Horm Res. 2003; 59: 149-155