Circulating and ovarian IGF binding proteins: Potential roles in normo-ovulatory cycles and in polycystic ovarian syndrome

Abstract

IGFs function as co-gonadotropins in the ovary, facilitating steroidogenesis and follicle growth. IGFBP-1 to -5 are expressed in human ovary and mostly inhibit IGF action in in vitro ovarian cell culture systems. In the clinical disorder of polycystic ovarian syndrome (PCOS), which is characterized by hyperandrogenemia, polycystic ovaries and anovulation, follicles have a higher androgen : estradiol (A : E₂) content and growth is arrested at the small antral stage. In the PCOS follicle, follicle stimulating hormone (FSH) and IGF levels are in the physiologic range, and even in the face of abundant androstenedione (AD) substrate, aromatase activity and E₂ production are low. When PCOS granulosa are removed from their ovarian environment, they respond normally or hyperrespond to FSH. It has been postulated that an inhibitor of IGF's synergistic actions with FSH on aromatase activity may be one (or more) of the IGFBPs, which contributes to the arrested state of follicular development commonly observed in this disorder. High levels of IGFBP-2 and IGFBP-4 are present in follicular fluid (FF) from androgen-dominant follicles (FF_a) from normally cycling women and in women with PCOS. This is in marked contrast to the near absence of these IGFBPs in estrogen-dominant FF (FF_e), determined by Western ligand blotting. Regulation of granulosa-derived IGFBPs is effected by gonadotropins and insulin-like peptides. In addition, an IGFBP-4 metallo-serine protease is present in FF_e, but not in FF_a in ovaries from normally cycling women and those with PCOS, although the IGFBP-4 protease is present in PCOS follicles hyperstimulated for in vitro fertilization. Recent studies demonstrate that IGF-II in FF_e is higher than in FF_a, whereas IGF-I, IGFBP-3 and IGFBP-1 levels do not differ, underscoring the importance of local IGF-II production by the granulosa and the importance of IGFBP-4 and IGFBP-2 in regulation of IGF-II action within the follicle during its developmental pathway as an E₂- or A-dominant follicle. In the androgen-treated female-to-male transsexual (TSX) model for PCOS, IGF-I, IGF-II, IGFBP-3 and IGFBP-1 levels do not differ in A-dominant follicles in TSX ovaries, compared to A-dominant follicles from normally cycling women. Furthermore, TSX follicles do not contain IGFBP-4 protease, similar to A-dominant follicles from normally cycling women and those with PCOS. In summary, A-dominant follicles contain physiologic levels of IGF-I and IGF-II, high levels of inhibitory IGFBPs and low levels of IGFBP-4 protease, thereby favoring low levels of bioavailable IGFs in these follicles. In contrast, maximal IGF bioavailability is maintained in the E-dominant follicle by increased IGF-II production, decreased IGFBP production and increased IGFBP-degradation.