SERUM AND FOLLICULAR-FLUID LEVELS OF INSULIN-LIKE GROWTH-FACTOR-I (IGF-I), IGF-II, AND IGF-BINDING-PROTEIN-1 AND IGF-BINDING-PROTEIN-3 DURING THE NORMAL MENSTRUAL-CYCLE

Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have important regulatory functions in ovarian follicular development . Although most studies have investigated the IGF system in ovarian ce lls in vitro, investigation of the IGF system in the peripheral circul ation and in follicles of varying sizes throughout the menstrual cycle in large numbers of subjects has been lacking. In the current study w e performed daily IGF-I, IGF-II, IGFBP-1, and IGFBP-3 measurements in 9 healthy regularly cycling volunteers throughout the menstrual cycle. In addition, we investigated IGF-I, IGF-II, IGFBP-1, and IGFBP-3 leve ls in 13 samples of androgen-dominant follicular fluid [FFa,; androste nedione to estradiol (AD:E(2) ratio, >4] and 19 samples of estrogen-do minant follicular fluid (FFe; AD:E(2) ratio, 4) obtained from 21 regul arly cycling subjects and in 18 samples of fluid from luteinizing foll icles obtained from patients undergoing in vitro fertilization (IVF) t reatment (FFivf). IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were measured us ing two-site immunoradiometric assays. No significant day to day diffe rences were observed in IGF-I, IGF-II, IGFBP-1, and IGFBP-3 levels acr oss the menstrual cycle. Median IGF-II levels in FFe (630 ng/mL; range , 212-1000) were significantly higher compared to those in FFa (474 ng /mL; range, 272-603; P = 0.002). Median IGFBP-3 levels in FFe (2955 ng /mL; range, 388-3448) were also significantly higher than those in FFa (2352 ng/mL; range, 756-2604; P = 0.003). Median IGF-I (192 ng/mL; ra nge, 29-256) and IGFBP-1 (12 ng/mL; range, 2-281) levels in FFe were n ot significantly different from those in FFa [149 (range, 22-232) and 21 (range, 5-32) ng/mL, respectively]. In contrast, significantly lowe r IGFBP-1 levels were found in FFe compared to FFivf (79 ng/mL; range, 57-234; P = 0.002), whereas there was no significant difference betwe en FFe and FFivf IGF-I, IGF-II, or IGFBP-3 levels, respectively. IGF-I I levels were correlated with follicle diameter (r = 0.52; P = 0.002), cycle day (r = 0.47; P = 0.006), E(2) levels (r = 0.53; P = 0.003), A D:E(2) ratio (r = -0.58; P = 0.001), and P concentrations (r = 0.60; P = 0.001) in all follicles, whereas no such correlations were found wi th IGF-I. In conclusion, as circulating levels of IGF-I, IGF-II, IGFBP -1, and IGFBP-3 are not menstrual cycle dependent, it is unlikely that these growth factors and these binding proteins play an endocrine rol e in cyclic ovarian follicle development, although both cycle-dependen t delivery to the ovary and modification of their actions locally with in the ovary cannot be excluded. With regard to FF, the findings that IGF-II levels in FFe are elevated compared to those in FFa and correla te with follicular functional status support a role for IGF-II during development of the dominant follicle. In addition, as IGFBP-3 in estro gen-dominant follicles mirrors the rise of IGF-II, this IGFBP may be a primary regulator of IGF-II action within the estrogen-dominant folli cle. Finally, the finding of elevated levels of IGFBP-1 in luteinizing (IVF) follicles suggests an important role for this peptide in corpus luteum regulation.