Stockpiling of Transitional and Classic Primary Follicles in Ovaries of Women with Polycystic Ovary Syndrome

Abstract

Recently, we proposed an oocyte-growth differentiation factor-9 hypothesis that predicts alterations in the initial stages of folliculogenesis in polycystic ovary syndrome (PCOS) ovaries. Here, we test this hypothesis by scoring the composition of follicles in normal and PCOS ovaries. Follicles were classified as primordial, transitional primary, classic primary, secondary, and Graafian. A total of 2274 follicles were scored. The total number of growing follicles was significantly greater in PCOS ovaries than normal, but the number of nongrowing primordial follicles did not differ. Consequently, the increase in growing follicles in PCOS cannot be explained by increased primordial follicle recruitment. Differential counts showed that the number of growing follicles at each stage of development was significantly greater: PCOS had 2.7-fold more primary, 1.8-fold more secondary, and 2-fold more Graafian follicles than normal. The greatest effect was on the classic primary follicles where the number was almost 5-fold greater in PCOS ovaries. The absence of apoptosis in normal and PCOS preantral follicles argues that the increase in growing follicles in PCOS cannot be explained by changes in atresia. We conclude, therefore, that primary follicle growth is abnormally slow in PCOS and the dynamics are reflected in a stockpiling of classic primary follicles.

Polycystic ovary syndrome in adolescents

“…It is not too difficult to identify biochemical pathways that may be disrupted in PCOS. There is evidence for an intrinsic disorder of ovarian folliculogenesis, [45][46][47] constitutive hypersecretion of androgens by theca cells 48,49 and disordered secretion and action of insulin 50 (Figure 1). There are, however, obvious problems in searching for candidate genes in PCOS: the heterogeneous nature of the syndrome has given rise disagreement about definition and diagnostic criteria; in addition expression of features of PCOS occurs predominantly in women of reproductive age and there is no clear male phenotypeFboth of which make family-based studies difficult.…”

Disordered follicle development in ovaries of prenatally androgenized ewes

“…Anovulation reflects the arrest of follicle development in the late antral stages but recent work from our group (Webber et al 2003), and that of Erickson and colleagues (Maciel et al 2004), has highlighted a disorder of early, preantral follicle development. The mechanism of disordered early folliculogenesis in polycystic ovaries remains uncertain but exposure to excess androgen must be considered as a possible aetiological factor.…”

Growth and differentiation factor 9 promotes oocyte growth at the primary but not the early secondary stage in three-dimensional follicle culture

“…A similar phenotype was also observed in sheep with homozygous mutations in GDF9 [18][19][20]. GDF9 might also play a role at the primary stage in human folliculogenesis, as follicles of women with PCOS have decreased GDF9 expression and demonstrate a slowing of the primary to secondary follicle transition [21][22][23]. Studies to define GDF9 effects on follicle growth in culture have shown mixed results.…”

“…Sustained growth of early follicles-specifically, late primary and early secondary follicles-to the antral stage has been achieved in vitro with organ culture [24,[43][44][45] or coculture of isolated follicles with ovarian stromal cells [46][47][48][49], mouse embryonic fibroblasts [50], multiple other follicles [25], or supplemented media [51]. Together, these findings suggest that follicle growth at the primary and early secondary stages is enhanced by, and perhaps dependent upon, factors from the surrounding ovarian environment in addition to the critical role played by the oocyte-derived factor GDF9 [6,7,[17][18][19][20][21][22][23].…”