Insulin-like growth factor-II mediates the steroidogenic and growth promoting actions of follicle stimulating hormone on human ovarian pre-antral follicles cultured in vitro.

FSH is important for ovarian antral follicle growth and steroidogenesis, processes in the human that are believed to be mediated by IGF-II. The objective of this study was to determine if human ovarian pre-antral follicles are also FSH- and IGF-II-responsive, since the clinical questions and mechanisms underlying the effects on the pre-antral follicle pool of exogenously administered gonadotropins for fertility therapy and elevated endogenous gonadotropins in the perimenopause remain unanswered. Class 2 preantral follicles were isolated from human premenopausal ovaries (n=6) and cultured in vitro with androstenedione and either no additives or with FSH or IGF-II. FSH (100 ng/mL) stimulated estradiol (E2) production by 3.58 +/- 0.4 fold over 48 hr, compared to controls without FSH. This effect was completely inhibited in the presence of the IGF-II antagonist, IGF binding protein-4 (IGFBP-4). IGF-II also stimulated E2 production by preantral follicles with doses as low as 1 ng/mL and within 24 hr of treatment. Maximal response of 3- to 9-fold above control was achieved with 100 ng/mL of IGF-II between 96-120 hr of culture. IGFBP-4 completely inhibited E2 production to basal levels. FSH stimulated IGF-II mRNA in pre-antral follicles about 4-fold, determined by RT-PCR. FSH also stimulated follicle growth, determined by light microscopy, 50-68% over 48 hr, compared to controls (P<0.001), a process that was inhibited in the presence of IGFBP-4. Cumulatively, these data support IGF-II as a mediator of FSH action on human preantral follicles.