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-beta 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.

Figure 1

Human oocytes matured in vitro with and without E2. (With permission: Tesarik J, Mendoza C. Nongenomic effects of 17β-estradiol on maturing human oocytes: relationship to oocyte developmental potential. J Clin Endocrinol Metab 1995;80:1438-1443)

Figure 2

Gene expression profiles of 6 normal (N1-N6) and PCOS (P1-P6) oocytes. A) Principal Component Analysis, B) Differentially expressed mRNAs in PCOS vs. normal oocytes. (With permission: Wood JR, Dumesic DA, Abbott DH, et al. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab 2007;92:705-713)

Figure 3

Correlation between intrafollicular insulin levels and BMI in women undergoing ovarian stimulation for IVF. (With permission: Dumesic DA, Schramm RD, Abbott DH. Early Origins of Polycystic Ovary Syndrome (PCOS). Reprod Fertil Dev 2005;17:349-360)

Figure 4

Percent human preantral follicles with GDF9 mRNA Expression.. *, P<0.05; **, P<0.01; ***, P<0.001. (With permission: Filho FLT, Baracat EC, Lee TH, 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)

Figure 5

A) Percent human follicles with AMH staining and B) mean intensity of AMH staining. a, P<0.005 vs. normal ovaries; b, P<0.005 vs. ovulatory PCO ovaries; c, P<0.005, d, P<0.05 vs. normal and ovulatory PCO ovaries. (With permission: Stubbs SA, 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 Copyright 2005, The Endocrine Society)