Implications of Polycystic Ovary Syndrome on Oocyte Development

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.

KEYWORDS

Polycystic ovary syndrome - follicle development - hyperandrogenism - hyperinsulinemia - oocyte maturation

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
• 2 McNatty K P, Smith P, Moore L G et al.. Oocyte-expressed genes affecting ovulation rate.  Mol Cell Endocrinol. 2005;  234 57-66
• 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
• 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
• 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
• 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
• 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
• 8 Dumesic D A, Schramm R D, Abbott D H. Early origins of polycystic ovary syndrome (PCOS).  Reprod Fertil Dev. 2005;  17 349-360
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 16 Gougeon A. Regulation of ovarian follicular development in primates: facts and hypothesis.  Endocr Rev. 1996;  17 121-155
• 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
• 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
• 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
• 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
• 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
• 22 Latham K E. Epigenetic modification and imprinting of the Mamm Genome during development.  Curr Top Dev Biol. 1999;  43 1-49
• 23 Moor R M, Dai Y, Lee C et al.. Oocyte maturation and embryonic failure.  Hum Reprod Update. 1998;  4 223-236
• 24 Albertini D F. Origins and manifestations of oocyte maturation competencies.  Reprod Biomed Online. 2003;  6 410-415
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 32 Assey R J, Hyttel P, Greve T et al.. Oocyte morphology in dominant and subordinate follicles.  Mol Reprod Dev. 1994;  37 335-344
• 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
• 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
• 35 Hyttel P, Fair T, Callesen H et al.. Oocyte growth, capacitation and final maturation in cattle.  Theriogenology. 1997;  47 23-32
• 36 Moor R M, Lee C, Dai Y F et al.. Antral follicles confer developmental competence on oocytes.  Zygote. 1996;  4 289-293
• 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
• 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
• 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
• 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
• 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
• 42 Stebbins-Boaz B, Richter J D. Translational control during early development.  Crit Rev Eukaryot Gene Expr. 1997;  7 73-94
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 65 Hickey T. Androgen Receptor Mediated Activity in the Ovary: Implications for Polycystic Ovary Syndrome [Ph.D. thesis]. Adelaide, Australia; University of Adelaidem 2006
• 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
• 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
• 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
• 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
• 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
• 71 Franks S, Mason H, Willis D. Follicular dynamics in the polycystic ovary syndrome.  Mol Cell Endocrinol. 2000;  163 49-52
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 90 Knight P G, Glister C. Potential local regulatory functions of inhibins, activins and follistatin in the ovary.  Reproduction. 2001;  121 503-512
• 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
• 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
• 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
• 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
• 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
• 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