EXPRESSION OF THE GENES ENCODING THE INSULIN-LIKE GROWTH-FACTORS (IGF-I AND IGF-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 t he genes encoding the IGFs, IGF receptors (IGFr), insulin receptor (Ir ), and IGF-binding proteins (IGFBPs-1-6) as well as the localization o f the gene products in specific cellular compartments of normal and PC OS human ovaries. Messenger ribonucleic acid (mRNA) was localized by i n situ hybridization with specific S-35-labeled human antisense RNA pr obes, 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 t ranscripts. Abundant IGF-Ir mRNA was found only in GC, IGF-IIr mRNA wa s found in both granulosa and thecal cells, and Ir mRNA was detected i n all cell types, including granulosa, thecal, and stromal cells. Loca lization of the gene products revealed no IGF-I immunoreactivity; howe ver, immunostaining for each of the other gene products was colocalize d with its corresponding mRNA. The cellular distribution of mRNA and p rotein in PCOS follicles was indistinguishable from that observed in s mall antral follicles from normal ovaries. In dominant follicles, howe ver, IGF-I mRNA was no longer detectable, but abundant IGF-II mRNA was expressed exclusively in GC. Although IGF-Ir mRNA was expressed in CC , IGF-IIr mRNA was found in both granulosa and thecal cells. In follic les taken from PCOS ovaries, no IGFBP-1 mRNA was detected, IGFBP-2 mRN A was abundant in both granulosa and thecal cells, moderate IGFBP-3 mR NA was found only in thecal cells, IGFBP-4 and -5 mRNAs were present i n all cellular compartments, and IGFBP-6 mRNA was not detected. Locali zation of the gene products by immunostaining revealed that each prote in 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 IGF BP-3 mRNA in both granulosa and thecal cells. Moderate expression of t he IGFBP-4 and IGFBP-5 genes was seen in all cell types, including str omal cells, but no IGFBP-6 mRNA was detected. Again, each of the gene products colocalized with its corresponding mRNA. We conclude the foll owing. 1) Although remarkable difference exist between PCOS follicles and dominant follicles, the expression of mRNAs encoding the IGFs, IGF rs, Ir, and IGFBPs and localization of the proteins are similar to tho se seen in small antral follicles of normal ovaries, suggesting that c ommon mechanisms may be involved in follicular maturational arrest in both situations. 2) In GC of both PCOS follicles and small antral foll icles of normal ovaries, no IGFBP-1 and IGFBP-3 mRNA were seen, wherea s abundant IGFBP-2 mRNA was expressed. Thus, secreted IGFBP-2 may func tion as an inhibitor of FSH action in the GC. 3) The presence of Ir mR NA and protein in all cellular compartments of the PCOS ovary lends su pport to an endocrine role of hyperinsulinemia in ovarian hyperandroge nism in PCOS.