INSULIN-LIKE GROWTH-FACTOR REGULATION OF HUMAN ENDOMETRIAL STROMAL CELL-FUNCTION - COORDINATE EFFECTS ON INSULIN-LIKE GROWTH-FACTOR BINDINGPROTEIN-1, CELL-PROLIFERATION AND PROLACTIN SECRETION

The insulin-like growth factor (IGF) autocrine/paracrine system is bel ieved to be involved in endometrial differentiation, but there is limi ted information on the specific cellular functions regulated by IGFs i n uterine tissues and their regulation of IGF-binding proteins (IGFBPs ). We have investigated the regulation by insulin, IGF-I, and IGF-II, of IGFBP secretion in human endometrial stromal cells decidualized in vitro, and examined the interrelationship between the induced changes in IGFBP levels and the biological responses of stromal cells to IGFs. IGFBPs in conditioned media were analyzed by Western ligand blotting, and IGFBP-1 was quantified by an immunoenzymometric assay (IEMA). In the absence of peptides, decidualized stromal cells secreted 25.5 +/- 3.2 mug/day per 10(6) cells of IGFBP-1. Insulin caused a dose-dependen t reduction of IGFBP-1 secretion (half-maximal inhibition at < 1 ng/ml ) to a maximum of 1 % of control values. Northern analysis using a spe cific cDNA probe showed the expression in decidualized stromal cells o f a single 1.5 kb transcript for IGFBP-1, which was absent in insulin- treated cells. The effects of IGF-I and IGF-II on IGFBP-1 secretion we re biphasic, with initial stimulation (200-250%) that peaked at 1 and 10 ng/ml, respectively, followed by inhibition at higher concentration s (half maximal inhibition at 3 ng/ml and 30 ng/nil, respectively). Th e decrease in IGFBP-1 levels in decidualized stromal cultures was asso ciated with the induction of mitogenesis by IGF-I and IGF-11, while IG F effects on prolactin secretion paralleled those of IGFBP-1 secretion , with stimulation (243-324%) in the low concentration range followed by inhibition at higher concentrations. These data indicate that endom etrial stromal cell IGFBP-I is regulated by insulin, at concentrations that are compatible with insulin acting via its own receptor, while t he effects of IGF-I and IGF-II on IGFBP-1 secretion, are suggestive of their acting probably through the type I IGF receptor. The present st udy describes distinct effects of the IGFs on stromal cell IGFBPs, tha t correlate with changes in the proliferative and secretory responses of decidualized stromal cells to the IGFs. Our findings suggest that c omplex IGF-IGFBP interactions may participate in the regulation of end ometrial cell function, and support a role for IGF-II in stromal cell mitogenesis during decidualization, and as a local regulator of decidu al cell function during the late secretory phase and early pregnancy.