Expression of the genes encoding the insulin-like growth factors (IGF-I and II), the IGF and insulin receptors, and IGF-binding proteins-1-6 and the localization of their gene products in normal and polycystic ovary syndrome ovaries

To discern the potential role of the insulin-like growth factors (IGFs) in polycystic ovary syndrome (PCOS), we examined the expression of the genes encoding the IGFs, IGF receptors (IGFr), insulin receptor (Ir), and IGF-binding proteins (IGFBPs-1-6) as well as the localization of the gene products in specific cellular compartments of normal and PCOS human ovaries. Messenger ribonucleic acid (mRNA) was localized by in situ hybridization with specific 35S-labeled human antisense RNA probes, and protein was detected by immunohistochemistry using specific antisera. Thecal cells, but not granulosa cells (GC), of small antral follicles (3-6 mm) from PCOS ovaries expressed both IGF-I and IGF-II transcripts. Abundant IGF-Ir mRNA was found only in GC, IGF-IIr mRNA was found in both granulosa and thecal cells, and Ir mRNA was detected in all cell types, including granulosa, thecal, and stromal cells. Localization of the gene products revealed no IGF-I immunoreactivity; however, immunostaining for each of the other gene products was colocalized with its corresponding mRNA. The cellular distribution of mRNA and protein in PCOS follicles was indistinguishable from that observed in small antral follicles from normal ovaries. In dominant follicles, however, IGF-I mRNA was no longer detectable, but abundant IGF-II mRNA was expressed exclusively in GC. Although IGF-Ir mRNA was expressed in GC, IGF-IIr mRNA was found in both granulosa and thecal cells. In follicles taken from PCOS ovaries, no IGFBP-1 mRNA was detected, IGFBP-2 mRNA was abundant in both granulosa and thecal cells, moderate IGFBP-3 mRNA was found only in thecal cells, IGFBP-4 and -5 mRNAs were present in all cellular compartments, and IGFBP-6 mRNA was not detected. Localization of the gene products by immunostaining revealed that each protein colocalized with its corresponding mRNA. The cellular distribution of IGFBP mRNA and protein in PCOS follicles was also indistinguishable from that in small antral follicles of normal ovaries, but remarkable differences were found in dominant follicles, where abundant IGFBP-1 mRNA was seen exclusively in GC, IGFBP-2 mRNA in thecal cells, and IGFBP-3 mRNA in both granulosa and thecal cells. Moderate expression of the IGFBP-4 and IGFBP-5 genes was seen in all cell types, including stromal cells, but no IGFBP-6 mRNA was detected. Again, each of the gene products colocalized with its corresponding mRNA. We conclude the following. 1) Although remarkable difference exist between PCOS follicles and dominant follicles, the expression of mRNAs encoding the IGFs, IGFrs, Ir, and IGFBPs and localization of the proteins are similar to those seen in small antral follicles of normal ovaries, suggesting that common mechanisms may be involved in follicular maturational arrest in both situations. 2) In GC of both PCOS follicles and small antral follicles of normal ovaries, no IGFBP- 1 and IGFBP-3 mRNA were seen, whereas abundant IGFBP-2 mRNA was expressed. Thus, secreted IGFBP-2 may function as an inhibitor of FSH action in the GC. 3) The presence of Ir mRNA and protein in all cellular compartments of the PCOS ovary lends support to an endocrine role of hyperinsulinemia in ovarian hyperandrogenism in PCOS.