Implications of Polycystic Ovary Syndrome on Oocyte Development

 

 Buy Article Permissions and Reprints

ABSTRACT

Human follicle development requires the recruitment of primordial follicles into a cohort of growing follicles from which one follicle is selected to ovulate a mature oocyte. During this developmental process, complex endocrine and intraovarian paracrine signals create a changing intrafollicular hormonal milieu. With this microenvironment, appropriate cumulus cell-oocyte signaling governs oocyte developmental competence, defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. Many of these mechanisms are perturbed in polycystic ovary syndrome (PCOS), a heterogeneous syndrome characterized by ovarian hyperandrogenism, hyperinsulinemia from insulin resistance, and reduced fecundity. In addition to these endocrinopathies, PCOS also is characterized by paracrine dysregulation of follicle development by intraovarian proteins of the transforming growth factor-β family. Consequently, PCOS patients undergoing ovarian stimulation for in vitro fertilization are at increased risks of impaired oocyte developmental competence, implantation failure, and pregnancy loss. Recent data demonstrate links between endocrine/paracrine factors and oocyte gene expression in PCOS and suggest that new clinical strategies to optimize developmental competence of PCOS oocytes should target correction of the entire follicle growth and oocyte development process.

REFERENCES

• 1 Hutt K J, McLaughlin E A, Holland M K. Kit ligand and c-Kit have diverse roles in mammalian oogenesis and folliculogenesis.  Mol Hum Reprod. 2006;  12 61-69
  CrossrefPubMedGoogle Scholar
• 2 McNatty K P, Smith P, Moore L G et al.. Oocyte-expressed genes affecting ovulation rate.  Mol Cell Endocrinol. 2005;  234 57-66
  CrossrefPubMedGoogle Scholar
• 3 Yan C, Wang P, DeMayo J et al.. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function.  Mol Endocrinol. 2001;  15 854-866
  CrossrefPubMedGoogle Scholar
• 4 Su Y Q, Wu X, O'Brien M J et al.. Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop.  Dev Biol. 2004;  276 64-73
  CrossrefPubMedGoogle Scholar
• 5 Sutton M L, Gilchrist R B, Thompson J G. Effects of in-vivo and in-vitro environments on the metabolism of the cumulus-oocyte complex and its influence on oocyte developmental capacity.  Hum Reprod Update. 2003;  9 35-48
  CrossrefPubMedGoogle Scholar
• 6 Sugiura K, Eppig J J. Society for Reproductive Biology Founders' Lecture. Control of metabolic cooperativity between oocytes and their companion granulosa cells by mouse oocytes.  Reprod Fertil Dev. 2005;  17 667-674
  CrossrefPubMedGoogle Scholar
• 7 Schramm R D, Bavister B D. A macaque model for studying mechanisms controlling oocyte development and maturation in human and nonhuman primates.  Hum Reprod. 1999;  14 2544-2555
  CrossrefPubMedGoogle Scholar
• 8 Dumesic D A, Schramm R D, Abbott D H. Early origins of polycystic ovary syndrome (PCOS).  Reprod Fertil Dev. 2005;  17 349-360
  CrossrefPubMedGoogle Scholar
• 9 Heijnen E MEW, Eijkemans M JC, Hughes E G et al.. A meta-analysis of outcomes of conventional IVF in women with polycstic ovary syndrome.  Hum Reprod Update. 2006;  12 13-21
  CrossrefPubMedGoogle Scholar
• 10 Sengoku K, Tamate K, Takuma N et al.. The chromosomal normality of unfertilized oocytes from patients with polycystic ovarian syndrome.  Hum Reprod. 1997;  12 474-477
  CrossrefPubMedGoogle Scholar
• 11 Ludwig M, Finas D F, Al-Hasani S et al.. Oocyte quality and treatment outcome in intracytoplasmic sperm injection cycles of polycystic ovarian syndrome patients.  Hum Reprod. 1999;  14 354-358
  CrossrefPubMedGoogle Scholar
• 12 Cano F, Garcia-Velasco J A, Millet A. Oocyte quality in polycystic ovaries revisited: identification of a particular subgroup of women.  J Assist Reprod Genet. 1997;  14 254-260
  PubMedGoogle Scholar
• 13 Faddy M J, Gosden R G. Modelling the dynamics of ovarian follicle utilization throughout life. In: Trounson AO, Gosden RG Biology and Pathology of the Oocyte. Role in Fertility and Reproductive Medicine. Cambridge, UK; Cambridge University Press 2003: 44-52
  Google Scholar
• 14 Gougeon A. The early stages of folliclar growth. In: Trounson AO, Gosden RG Biology and Pathology of the Oocyte. Role in Fertility and Reproductive Medicine. Cambridge, UK; Cambridge University Press 2003: 29-43
  Google Scholar
• 15 Durlinger A LL, Gruijters M J, Kramer P et al.. Anti-Mullerian hormone inhibits initiation of primordial follicle growth in the mouse ovary.  Endocrinology. 2002;  143 1076-1084
  CrossrefPubMedGoogle Scholar
• 16 Gougeon A. Regulation of ovarian follicular development in primates: facts and hypothesis.  Endocr Rev. 1996;  17 121-155
  CrossrefPubMedGoogle Scholar
• 17 Rice S, Ojha K, Whitehead S et al.. Stage-specific expression of androgen receptor, follicle-stimulating hormone receptor, and anti-mullerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries.  J Clin Endocrinol Metab. 2007;  92 1034-1040
  PubMedGoogle Scholar
• 18 Jakimiuk A J, Weitsman S R, Brzechffa P R et al.. Aromatase mRNA expression in individual follicles from polycystic ovaries.  Mol Hum Reprod. 1998;  4 1-8
  CrossrefPubMedGoogle Scholar
• 19 Hillier S G, Whitelaw P F, Smyth C D. Follicular oestrogen synthesis: the ‘two-cell, two-gonadotropin' model revisited.  Mol Cell Endocrinol. 1994;  100 51-54
  CrossrefPubMedGoogle Scholar
• 20 Zachow R J, Magoffin D A. Ovarian androgen biosynthesis: paracrine/autocrine regulation. In: Azziz R, Nestler JE, Dewailly D Androgen Excess Disorders in Women. Philadelphia, PA; Lippincott-Raven 1997: 13-22
  Google Scholar
• 21 Willis D S, Watson H, Mason H D et al.. Premature response to LH of granulosa cells from anovulatory women with polycystic ovaries: relevance to mechanism of anovulation.  J Clin Endocrinol Metab. 1998;  83 3984-3991
  CrossrefPubMedGoogle Scholar
• 22 Latham K E. Epigenetic modification and imprinting of the Mamm Genome during development.  Curr Top Dev Biol. 1999;  43 1-49
  PubMedGoogle Scholar
• 23 Moor R M, Dai Y, Lee C et al.. Oocyte maturation and embryonic failure.  Hum Reprod Update. 1998;  4 223-236
  CrossrefPubMedGoogle Scholar
• 24 Albertini D F. Origins and manifestations of oocyte maturation competencies.  Reprod Biomed Online. 2003;  6 410-415
  PubMedGoogle Scholar
• 25 Bachvarova R. Gene expression during oogenesis and oocyte development in mammals. In: Browder LW Developmental Biology: A Comprehensive Synthesis. New York, NY; Plenum 1985 1: 453-524
  Google Scholar
• 26 Wickramasinghe D, Ebert K M, Albertini D F. Meiotic competence acquisition is associated with the appearance of M-phase characteristics in growing mouse oocytes.  Dev Biol. 1991;  143 162-172
  CrossrefPubMedGoogle Scholar
• 27 Fair T, Hyttel P, Greve T et al.. Nucleus structure and transcriptional activity in relation to oocyte diameter in cattle.  Mol Reprod Dev. 1996;  43 503-512
  CrossrefPubMedGoogle Scholar
• 28 Pavlok A, Lucas-Hahn A, Niemann H. Fertilization and developmental competence of bovine oocytes derived from different categories of antral follicles.  Mol Reprod Dev. 1992;  31 63-67
  CrossrefPubMedGoogle Scholar
• 29 Su Y Q, Sugiura K, Woo Y et al.. Selective degradation of transcripts during meiotic maturation of mouse oocytes.  Dev Biol. 2007;  302 104-117
  CrossrefPubMedGoogle Scholar
• 30 Gandolfi T A, Gandolfi F. The maternal legacy to the embryo: cytoplasmic components and their effects on early development.  Theriogenology. 2001;  55 1255-1276
  CrossrefPubMedGoogle Scholar
• 31 Tomek W, Torner H, Kanitz W. Comparative analysis of protein synthesis, transcription and cytoplasmic polyadenylation of mRNA during maturation of bovine oocytes in vitro.  Reprod Domest Anim. 2002;  37 86-91
  CrossrefPubMedGoogle Scholar
• 32 Assey R J, Hyttel P, Greve T et al.. Oocyte morphology in dominant and subordinate follicles.  Mol Reprod Dev. 1994;  37 335-344
  CrossrefPubMedGoogle Scholar
• 33 Osborn J C, Moor R M. The role of steroid signals in the maturation of mammalian oocytes.  J Steroid Biochem. 1983;  19 133-137
  PubMedGoogle Scholar
• 34 Mattioli M, Galeati G, Bacci M L et al.. Follicular factors influence oocyte fertilizability by modulating the intercellular cooperation between cumulus cells and oocyte.  Gamete Res. 1988;  21 223-232
  CrossrefPubMedGoogle Scholar
• 35 Hyttel P, Fair T, Callesen H et al.. Oocyte growth, capacitation and final maturation in cattle.  Theriogenology. 1997;  47 23-32
  CrossrefPubMedGoogle Scholar
• 36 Moor R M, Lee C, Dai Y F et al.. Antral follicles confer developmental competence on oocytes.  Zygote. 1996;  4 289-293
  PubMedGoogle Scholar
• 37 Schramm R D, Bavister B D. FSH-priming of rhesus monkeys enhances meiotic and developmental competence of oocytes matured in vitro.  Biol Reprod. 1994;  51 904-912
  CrossrefPubMedGoogle Scholar
• 38 Wynn P, Picton H M, Krapez J A et al.. Pretreatment with follicle stimulating hormone promotes the numbers of human oocytes reaching metaphase II by in vitro maturation.  Hum Reprod. 1998;  13 3132-3138
  CrossrefPubMedGoogle Scholar
• 39 Ectors F J, Vanderzwalmen P, Van Hoeck J V et al.. Relationship of human follicular diameter with oocyte fertilization and development after in-vitro fertilization or intracytoplasmic sperm injection.  Hum Reprod. 1997;  12 2002-2005
  CrossrefPubMedGoogle Scholar
• 40 Bergh C, Broden H, Lundin K et al.. Comparison of fertilization, cleavage and pregnancy rates of oocytes from large and small follicles.  Hum Reprod. 1998;  13 1912-1915
  CrossrefPubMedGoogle Scholar
• 41 Arnot A M, Vandekerckhove P, DeBono M A et al.. Follicular volume and number during in-vitro fertilization: association with oocyte developmental capacity and pregnancy rate.  Hum Reprod. 1995;  10 256-261
  PubMedGoogle Scholar
• 42 Stebbins-Boaz B, Richter J D. Translational control during early development.  Crit Rev Eukaryot Gene Expr. 1997;  7 73-94
  PubMedGoogle Scholar
• 43 Dumesic D A, Schramm R D, Bird I M et al.. Reduced intrafollicular androstenedione and estradiol levels in early-treated prenatally androgenized female rhesus monkeys receiving FSH therapy for in vitro fertilization.  Biol Reprod. 2003;  69 1213-1219
  CrossrefPubMedGoogle Scholar
• 44 Vendola K A, Zhou J, Adesanya O O et al.. Androgens stimulate early stages of follicle growth in the primate ovarian.  J Clin Invest. 1998;  101 2622-2629
  CrossrefPubMedGoogle Scholar
• 45 Weil S J, Vendola K, Zhou J et al.. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations.  J Clin Endocrinol Metab. 1998;  83 2479-2485
  CrossrefPubMedGoogle Scholar
• 46 Weil S, Vendola K, Zhou J et al.. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development.  J Clin Endocrinol Metab. 1999;  84 2951-2956
  CrossrefPubMedGoogle Scholar
• 47 Vendola K, Zhou J, Wang J et al.. Androgens promote insulin-like growth factor-I and insulin-like growth factor-I receptor gene expression in the primate ovary.  Hum Reprod. 1999;  14 2328-2332
  CrossrefPubMedGoogle Scholar
• 48 Vendola K, Zhou J, Wang J et al.. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary.  Biol Reprod. 1999;  61 353-357
  PubMedGoogle Scholar
• 49 Jonard S, Robert Y, Cortet-Rudelli C et al.. Ultrasound examination of polycystic ovaries: is it worth counting the follicles?.  Hum Reprod. 2003;  18 598-603
  CrossrefPubMedGoogle Scholar
• 50 Dumesic D A, Damario M A, Session D R et al.. Ovarian morphology and serum hormone markers as predictors of ovarian follicle recruitment by gonadotropins for in vitro fertilization.  J Clin Endocrinol Metab. 2001;  86 2538-2543
  CrossrefPubMedGoogle Scholar
• 51 Nelson V L, Qin K, 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
  CrossrefPubMedGoogle Scholar
• 52 Eden J A, Jones J, Carter G D et al.. Follicular fluid concentrations of insulin-like growth factor 1, epidermal growth factor, transforming growth factor-alpha and sex-steroids in volume matched normal and polycystic human follicles.  Clin Endocrinol (Oxf). 1990;  32 395-405
  PubMedGoogle Scholar
• 53 Webber L J, Stubbs S, Stark J et al.. Formation and early development of follicles in the polycystic ovary.  Lancet. 2003;  362 1017-1021
  CrossrefPubMedGoogle Scholar
• 54 Maciel G A, Baracat E C, Benda J A et al.. Stockpiling of transitional and classic primary follicles in ovaries of women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2004;  89 5321-5327
  CrossrefPubMedGoogle Scholar
• 55 Tesarik J, Mendoza C. Nongenomic effects of 17B-estradiol on maturing human oocytes: relationship to oocyte developmental potential.  J Clin Endocrinol Metab. 1995;  80 1438-1443
  CrossrefPubMedGoogle Scholar
• 56 Tesarik J, Mendoza C. Direct non-genomic effects of follicular steroids on maturing human oocytes: oestrogen versus androgen antagonism.  Hum Reprod Update. 1997;  3 95-100
  CrossrefPubMedGoogle Scholar
• 57 Andersen C Y. Characteristics of human follicular fluid associated with successful conception after in vitro fertilization.  J Clin Endocrinol Metab. 1993;  77 1227-1234
  CrossrefPubMedGoogle Scholar
• 58 Jakimiuk A J, Weitsman S R, Magoffin D A. 5a-Reductase activity in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1999;  84 2414-2418
  CrossrefPubMedGoogle Scholar
• 59 Agarwal S K, Judd H L, Magoffin D A. A mechanism for the suppression of estrogen production in polycystic ovary syndrome.  J Clin Endocrinol Metab. 1996;  81 3686-3691
  CrossrefPubMedGoogle Scholar
• 60 Dumesic D A, Schramm R D, Peterson E et al.. Impaired developmental competence of oocytes in adult prenatally androgenized female rhesus monkeys undergoing gonadotropin stimulation for in vitro fertilization.  J Clin Endocrinol Metab. 2002;  87 1111-1119
  CrossrefPubMedGoogle Scholar
• 61 Zheng P, Wei S, Bavister B D et al.. 17β-estradiol and progesterone improve in-vitro cytoplasmic maturation of oocytes from unstimulated prepubertal and adult rhesus monkeys.  Hum Reprod. 2003;  18 2137-2144
  CrossrefPubMedGoogle Scholar
• 62 Dumesic D A, Schramm R D, Abbott D H. Steroid and oocyte development. In: Filicori M Updates in Infertility Treatment 2004. Bologna, Italy; Medimond 2005: 457-475
  Google Scholar
• 63 Foong S C, Abbott D H, Zschunke M A et al.. Follicle luteinization in hyperandrogenic follicles of polycystic ovary syndrome (PCOS) patients undergoing gonadotropin therapy for in vitro fertilization.  J Clin Endocrinol Metab. 2006;  91 2327-2333
  CrossrefPubMedGoogle Scholar
• 64 Wood J R, Dumesic D A, Abbott D H et al.. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis.  J Clin Endocrinol Metab. 2007;  92 705-713
  PubMedGoogle Scholar
• 65 Hickey T. Androgen Receptor Mediated Activity in the Ovary: Implications for Polycystic Ovary Syndrome [Ph.D. thesis]. Adelaide, Australia; University of Adelaidem 2006
  Google Scholar
• 66 Phy J L, Conover C A, Abbott D H et al.. Insulin and messenger ribonucleic acid expression of insulin receptor isoforms in ovarian follicles from nonhirsute ovulatory women and polycystic ovary syndrome patients.  J Clin Endocrinol Metab. 2004;  89 3561-3566
  CrossrefPubMedGoogle Scholar
• 67 Samoto T, Maruo T, Ladines-llave C et al.. Insulin receptor expression in the follicular and stroma compartments of the human ovary over the course of follicular growth, regression, and atresia.  Endocr J. 1993;  40 715-726
  PubMedGoogle Scholar
• 68 Kezele P R, Nilsson E E, Skinner M K. Insulin but not insulin-like growth factor-I promotes the primordial to primary follicle transition.  Mol Cell Endocrinol. 2002;  192 37-43
  CrossrefPubMedGoogle Scholar
• 69 Balen A H, Conway G S, Homburg R, Legro R S. Polycystic Ovary Syndrome. A Guide to Clinical Management. London, UK; Taylor & Francis 2005: 47-67
  Google Scholar
• 70 Franks S, Gilling-Smith C, Watson H et al.. Insulin action in the normal and polycystic ovary.  Endocrinol Metab Clin North Am. 1999;  28 361-378
  CrossrefPubMedGoogle Scholar
• 71 Franks S, Mason H, Willis D. Follicular dynamics in the polycystic ovary syndrome.  Mol Cell Endocrinol. 2000;  163 49-52
  PubMedGoogle Scholar
• 72 Eppig J J, O'Brien M J, Pendola F L et al.. Factors affecting the developmental competence of mouse oocytes grown in vitro: follicle stimulating hormone and insulin.  Biol Reprod. 1998;  59 1445-1453
  CrossrefPubMedGoogle Scholar
• 73 Jakimiuk A J, Weitsman S R, Navab A et al.. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overproduced in thecal and granulosa cells from polycystic ovaries.  Clin Endocrinol Metab. 2001;  86 1318-1323
  PubMedGoogle Scholar
• 74 Kjotrod S B, During V V, Carlsen S M. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study.  Hum Reprod. 2004;  19 1315-1322
  CrossrefPubMedGoogle Scholar
• 75 Tang T, Glanville J, Orsi N et al.. The use of metformin for women with PCOS undergoing IVF treatment.  Hum Reprod. 2006;  21 1416-1425
  CrossrefPubMedGoogle Scholar
• 76 Legro R S, Barnhart H X, Schlaff W D Cooperative Multicenter Reproductive Medicine Network et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.  N Engl J Med. 2007;  356 551-566
  CrossrefPubMedGoogle Scholar
• 77 Knight P G, Glister C. Local roles of TGF-β superfamily members in the control of ovarian follicle development.  Anim Reprod Sci. 2003;  78 165-183
  PubMedGoogle Scholar
• 78 Elvin J A, Yan C, Matzuk M M. Oocyte-expressed TGF-beta superfamily members in female fertility.  Mol Cell Endocrinol. 2000;  159 1-5
  CrossrefPubMedGoogle Scholar
• 79 Hayashi M, McGee E A, Min G et al.. Recombinant growth differentiation factor-9 (GDF-9) enhances growth and differentiation of cultured early ovarian follicles.  Endocrinology. 1999;  140 1236-1244
  CrossrefPubMedGoogle Scholar
• 80 Vitt U A, Hayashi M, Klein C et al.. Growth differentiation factor-9 stimulates proliferation but suppresses the follicle-stimulating hormone-induced differentiation of cultured granulosa cells from small antral and preovulatory rat follicles.  Biol Reprod. 2000;  62 370-377
  PubMedGoogle Scholar
• 81 Hreinsson J G, Scott J E, Rasmussen C et al.. Growth differentiation factor-9 promotes the growth, development, and survival of human ovarian follicles in organ culture.  J Clin Endocrinol Metab. 2002;  87 316-321
  CrossrefPubMedGoogle Scholar
• 82 Aaltonen J, Laitinen M P, Vuojolainen K et al.. Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis.  J Clin Endocrinol Metab. 1999;  84 2744-2750
  CrossrefPubMedGoogle Scholar
• 83 Teixeira Filho F L, Baracat E C, Lee T H et al.. Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 1337-1344
  CrossrefPubMedGoogle Scholar
• 84 Stubbs S A, Hardy K, Da Silva-Buttkus P et al.. Anti-mullerian hormone protein expression is reduced during the initial stages of follicle development in human polycystic ovaries.  J Clin Endocrinol Metab. 2005;  90 5536-5543
  CrossrefPubMedGoogle Scholar
• 85 Weenen C, Laven J S, Von Bergh A R et al.. Anti-mullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment.  Mol Hum Reprod. 2004;  10 77-83
  CrossrefPubMedGoogle Scholar
• 86 Fanchin R, Louafi N, Lozano D HM et al.. Per-follicle measurements indicate that anti-mullerian hormone secretion is modulated by the extent of follicular development and luteinization and may reflect qualitatively the ovarian follicular status.  Fertil Steril. 2005;  84 167-173
  CrossrefPubMedGoogle Scholar
• 87 Eldar-Geva T, Margalioth E J, Gal M et al.. Serum anti-mullerian hormone levels during controlled ovarian hyperstimulation in women with polycystic ovaries with and without hyperandrogenism.  Hum Reprod. 2005;  20 1814-1819
  CrossrefPubMedGoogle Scholar
• 88 Durlinger A L, Kramer P, Karels B et al.. Control of primordial follicle recruitment by anti-Mullerian hormone in the mouse ovary.  Endocrinology. 1999;  140 5789-5798
  CrossrefPubMedGoogle Scholar
• 89 Fortune J E. The early stages of follicular development: activation of primordial follicles and growth of preantral follicles.  Anim Reprod Sci. 2003;  78 135-163
  CrossrefPubMedGoogle Scholar
• 90 Knight P G, Glister C. Potential local regulatory functions of inhibins, activins and follistatin in the ovary.  Reproduction. 2001;  121 503-512
  CrossrefPubMedGoogle Scholar
• 91 Sadatsuki M, Tsutsumi O, Yamada R et al.. Local regulatory effects of activin A and follistatin on meiotic maturation of rat oocytes.  Biochem Biophys Res Commun. 1993;  196 388-395
  CrossrefPubMedGoogle Scholar
• 92 Norman R J, Milner C R, Groome N P et al.. Circulating follistatin concentrations are higher and activin levels are lower in polycystic ovarian syndrome.  Hum Reprod. 2001;  16 668-672
  CrossrefPubMedGoogle Scholar
• 93 Eldar-Geva T, Spitz I M, Groome N P et al.. Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome.  Hum Reprod. 2001;  16 2552-2556
  CrossrefPubMedGoogle Scholar
• 94 Schneyer A L, Fujiwara T, Fox J et al.. Dynamic changes in the intrafollicular inhibin/activin/follistatin axis during human follicular development: relationship to circulating hormone levels.  J Clin Endocrinol Metab. 2000;  85 3319-3330
  CrossrefPubMedGoogle Scholar
• 95 Lambert-Messerlian G, Taylor A, Leykin L et al.. Characterization of intrafollicular steroid hormones, inhibin, and follistatin in women with and without polycystic ovarian syndrome following gonadotropin stimulation.  Biol Reprod. 1997;  57 1211-1216
  CrossrefPubMedGoogle Scholar
• 96 Welt C K, Taylor A E, Fox J et al.. Follicular arrest in polycystic ovary syndrome is associated with deficient inhibin A and B biosynthesis.  J Clin Endocrinol Metab. 2005;  90 5582-5587
  CrossrefPubMedGoogle Scholar

Daniel A DumesicM.D. 

Reproductive Medicine and Infertility Associates

2101 Woodwinds Drive, Woodbury, MN 55125

Email: danieldumesic@aol.com