Ovary

Insulin-Like Growth Factor (IGF) 2 Stimulates Steroidogenesis and Mitosis of Bovine Granulosa Cells Through the IGF1 Receptor: Role of Follicle-Stimulating Hormone and IGF2 Receptor

Abstract
Little is known regarding the role of insulin-like growth factor 2 (IGF2) and regulation of the IGF2 receptor (IGF2R) during follicular development. Granulosa cells were collected from small (1- 5 mm) and large (8 - 22 mm) bovine follicles, treated with IGF2 for 1 to 2 days in serum-free medium, and steroid production, cell proliferation, specific ¹²⁵I-IGF2 binding, and gene expression quantified. IGF2 increased both estradiol and progesterone production by granulosa cells, and cells from large follicles were more responsive to the effects of IGF2 than those from small follicles. Abundance of aromatase (CYP19A1) mRNA was stimulated by IGF2 and IGF1. The effective dose (ED₅₀) of IGF2 stimulating 50% of the maximal estradiol production was 63 ng/ml for small follicles and 12 ng/ml for large follicles, and these values were not affected by FSH. The ED₅₀ of IGF2 for progesterone production was 20 ng/ml for both small and large follicles. IGF2 also increased proliferation of granulosa cells by 2- to 3-fold as determined by increased cell numbers and ³H-thymidine incorporation into DNA. Treatment with IGF1R antibodies reduced the stimulatory effect of IGF2 and IGF1 on estradiol production and cell proliferation. Specific receptors for ¹²⁵I-IGF2 existed in granulosa cells and two-day treatment with estradiol, FSH or cortisol had no significant effect on specific ¹²⁵I-IGF2 binding. Also, FSH treatment of small and large follicle granulosa cells had no effect on IGF2R mRNA levels whereas IGF1 decreased IGF2R mRNA and specific ¹²⁵I-IGF2 binding. Granulosa cell IGF2R mRNA abundance was threefold greater in small than large follicles. These findings support the hypothesis that both IGF2 and its receptor may play a role in granulosa cell function during follicular development. In particular, increased free IGF1 in developing follicles may decrease synthesis of IGF2R thereby allowing for more IGF2 to be bioavailable (free) for induction of steroidogenesis and mitogenesis via the IGF1R.

Key words: Follicle • Follicular development • Granulosa cells • Insulin-like growth factor receptor

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