Ontogeny of the ovary in polycystic ovary syndrome
2013; Elsevier BV; Volume: 100; Issue: 1 Linguagem: Inglês
10.1016/j.fertnstert.2013.02.011
ISSN1556-5653
AutoresDaniel A. Dumesic, JoAnne S. Richards,
Tópico(s)Ovarian cancer diagnosis and treatment
ResumoActivation of primordial follicles into the growing pool, selection of the dominant follicle, and its eventual ovulation require complex endocrine and metabolic interactions as well as intraovarian paracrine signals to coordinate granulosa cell proliferation, theca cell differentiation, and oocyte maturation. Early preantral follicle development relies mostly upon mesenchymal-epithelial cell interactions, intraovarian paracrine signals, and oocyte-secreted factors, whereas development of the antral follicle depends on circulating gonadotropins as well as locally derived regulators. In women with polycystic ovary syndrome (PCOS), ovarian hyperandrogenism, hyperinsulinemia from insulin resistance, and altered intrafollicular paracrine signaling perturb the activation, survival, growth, and selection of follicles, causing accumulation of small antral follicles within the periphery of the ovary, giving it a polycystic morphology. Altered adipocyte-ovarian interactions further compound these adverse events on follicle development and also can harm the oocyte, particularly in the presence of increased adiposity. Finally, endocrine antecedents of PCOS occur in female infants born to mothers with PCOS, which suggests that interactions between genes and the maternal-fetal hormonal environment may program ovarian function after birth. Activation of primordial follicles into the growing pool, selection of the dominant follicle, and its eventual ovulation require complex endocrine and metabolic interactions as well as intraovarian paracrine signals to coordinate granulosa cell proliferation, theca cell differentiation, and oocyte maturation. Early preantral follicle development relies mostly upon mesenchymal-epithelial cell interactions, intraovarian paracrine signals, and oocyte-secreted factors, whereas development of the antral follicle depends on circulating gonadotropins as well as locally derived regulators. In women with polycystic ovary syndrome (PCOS), ovarian hyperandrogenism, hyperinsulinemia from insulin resistance, and altered intrafollicular paracrine signaling perturb the activation, survival, growth, and selection of follicles, causing accumulation of small antral follicles within the periphery of the ovary, giving it a polycystic morphology. Altered adipocyte-ovarian interactions further compound these adverse events on follicle development and also can harm the oocyte, particularly in the presence of increased adiposity. Finally, endocrine antecedents of PCOS occur in female infants born to mothers with PCOS, which suggests that interactions between genes and the maternal-fetal hormonal environment may program ovarian function after birth. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/dumesicd-ontogeny-of-the-ovary-pcos/Polycystic ovary syndrome (PCOS) is the most common cause of infertility in women (1Adams J. 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According to the Rotterdam criteria, PCOS is characterized by two of the following three features: [1] clinical or biochemical hyperandrogenism, [2] oligoanovulation, and [3] polycystic ovaries (PCO), excluding other endocrinopathies (5The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).Hum Reprod. 2004; 19: 41-47Crossref PubMed Scopus (1595) Google Scholar). Patients with PCOS also often present with elevated serum levels of luteinizing hormone (LH) and insulin. Although primordial follicles in the ovaries of PCOS patients leave the resting pool, most arrest at the small antral stage preceding dominant follicle selection, giving rise to many small follicles forming a ring around the ovary as a characteristic of PCO. Abnormal follicle growth in PCOS accompanies elevated levels of LH, insulin, and androgens; altered expression of transforming growth factor-β (TGF-β) family members; and comparatively low levels of follicle-stimulating hormone (FSH) (4Goodarzi M.O. Dumesic D.A. Chazenbalk G. Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis.Nat Rev Endocrinol. 2011; 7: 219-231Crossref PubMed Scopus (186) Google Scholar, 6Dumesic D.A. Padmanabhan V. Abbott D.H. Polycystic ovary syndrome and oocyte developmental competence.Obstet Gynecol Surv. 2008; 63: 39-48Crossref PubMed Scopus (25) Google Scholar). Studies have indicated that the expression and impact of these factors may vary in PCOS patients by phenotype and may be further influenced by the degree of adiposity (7Carmina E. Chu M.C. Longo R.A. Rini G.B. Lobo R.A. 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Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications.Endocr Rev. 2012; 33: 981-1030Crossref PubMed Scopus (81) Google Scholar).This review integrates what is currently known about normal follicular development with specific events that are altered in the follicles of PCOS patients. Mechanisms by which LH hypersecretion, hyperandrogenism, hyperinsulinemia, and TGF-β-related events alter ovarian follicle development are discussed, along with the potential roles of the insulin-like growth factor-I (IGF-I)/AKT/Forehead BoxO (FOXO) pathway and WNT signaling in these events. Due to space limitations, not all aspects of follicle development are covered in depth.Preantral follicle developmentOverviewPrimordial follicles are recruited into a cohort of growing follicles, from which one antral follicle is selected to become dominant while the others undergo atresia. Each primordial follicle contains an oocyte arrested at the diplotene stage of prophase one, surrounded by squamous granulosa cells. With follicle growth, the oocyte begins to synthesize messenger ribonucleic acid (mRNA), while squamous granulosa cells enlarge into a complete single layer of cuboidal granulosa cells, forming the primary follicle (11Faddy M.J. Gosden R.G. Modelling the dynamics of ovarian follicle utilization throughout life.in: Trounson A.O. Gosden R.G. Biology and pathology of the oocyte role in fertility and reproductive medicine. Cambridge University Press, Cambridge2003: 44-52Google Scholar, 12Gougeon A. The early stages of folliclar growth.in: Trounson A.O. Gosden R.G. Biology and pathology of the oocyte role in fertility and reproductive medicine. Cambridge University Press, Cambridge2003: 29-43Google Scholar).The Primordial to Primary TransitionPrimordial follicles can remain in the quiescent “resting” stage for many years. 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Whether this initial transition process is altered in the ovaries of PCOS patients remains unclear.Formation of Primary FolliclesOnce follicles leave the primordial stage to enter the growing pool, specific changes in the oocyte, granulosa cell, and theca cell functions occur, including [1] transition of granulosa cells from a flattened fibroblastic-like morphology to a cuboidal shape, [2] appearance of the zona pellucida, and eventually [3] formation of the theca cell layer external to granulosa cells and resting upon the basal lamina (Fig. 1).Formation of the theca cell layer in primary follicles critically depends on oocyte-derived growth differentiation factor 9 (GDF9) (28Elvin J.A. Clark A.T. Wang P. Wolfman N.M. Matzuk M.M. Paracrine actions of growth differentiation factor-9 in the mammalian ovary.Mol Endocrinol. 1999; 13: 1035-1048Crossref PubMed Google Scholar, 29Edson M.A. Nagaraja A.K. Matzuk M.M. 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Growth differentiation factor 9 promotes rat preantral follicle growth by up-regulating follicular androgen biosynthesis.Endocrinology. 2009; 150: 2740-2748Crossref PubMed Scopus (25) Google Scholar).Given this background, hyperandrogenism, hyperinsulinemia, and/or LH hypersecretion in PCOS patients would be expected to stimulate early follicle development, increase Fshr expression prematurely or to an exaggerated level, and render granulosa cells prematurely more responsive to FSH, perhaps through enhanced FSH-stimulated cyclic adenosine 3′:5′ monophosphate (cAMP) production (57Jonassen J.A. Bose K. Richards J.S. Enhancement and desensitization of hormone-responsive adenylate cyclase in granulosa cells of preantral and antral ovarian follicles: effects of estradiol and follicle-stimulating hormone.Endocrinology. 1982; 111: 74-79Crossref PubMed Google Scholar, 58Fitzpatrick S.L. Richards J.S. Regulation of cytochrome P450 aromatase messenger ribonucleic acid and activity by steroids and gonadotropins in rat granulosa cells.Endocrinology. 1991; 129: 1452-1462Crossref PubMed Google Scholar). Conversely, the ability of AMH to decrease the expression of Fshr and the response of granulosa cells to FSH (59Pellatt L. Rice S. Dilaver N. Heshri A. Galea R. Brincat M. et al.Anti-müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells.Fertil Steril. 2011; 96: 1246-1251Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar) would be expected to blunt the effects of FSH, at least temporarily, in early growing follicles but not necessarily in PCOS follicles (as will be discussed).In support of this, in vitro studies of PCOS theca cells show intrinsically increased androgen biosynthesis and augmented expression of several steroidogenic enzymes (60Nelson V.L. Legro R.S. Strauss 3rd, J.F. McAllister J.M. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries.Mol Endocrinol. 1999; 13: 946-957Crossref PubMed Google Scholar, 61Nelson V.L. Qin K.N. Rosenfield R.L. Wood J.R. Penning T.M. Legro R.S. 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: 5925-5933Crossref PubMed Scopus (193) Google Scholar), presumably from the enhancing effects of the retinoic acid pathway (47Wickenheisser J.K. Nelson-DeGrave V.L. Hendricks K.L. Legro R.S. Strauss J.F. McAllister J.M. Retinoids and retinol differentially regulate steroid biosynthesis in ovarian theca cells isolated from normal cycling women and women with polycystic ovary syndrome.J Clin Endocrinol Metab. 2005; 90: 4858-4865Crossref PubMed Scopus (24) Google Scholar) and dysregulation of theca cell mitogen activated protein kinase signaling (62Nelson-Degrave V.L. Wickenheisser J.K. Hendricks K.L. Asano T. Fujishiro M. Legro R.S. et al.Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome.Mol Endocrinol. 2005; 19: 379-390Crossref PubMed Scopus (57) Google Scholar). However, androgen production has not been established for normal or PCOS primordial or primary follicles, and reports using in situ hybridization indicate that the ovaries of anovulatory women with PCOS have increased primary follicle growth with reduced oocyte GDF-9 mRNA (63Stubbs S.A. Stark J. Dilworth S.M. Franks S. Hardy K. Abnormal preantral folliculogenesis in polycystic ovaries is associated with increased granulosa cell division.J Clin Endocrinol Metab. 2007; 92: 4418-4426Crossref PubMed Scopus (34) Google Scholar, 64Filho F.L.T. Baracat E.C. Lee T.H. Suh C.S. Matsui M. Chang R.J. et al.Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome.J Clin Endocrinol Metab. 2002; 87: 1337-1344Crossref PubMed Scopus (115) Google Scholar). Lower levels of GDF9 in PCOS follicles at this stage might be expected to reduce theca cell organization or androgen production, but this has not yet been investigated.Insulin may compensate for reduced GDF9. Furthermore, histologic examination of human ovaries from women with P
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