Ovary

Insulin-Like Growth Factor Binding Protein 4 Expression Parallels Luteinizing Hormone Receptor Expression and Follicular Luteinization in the Primate Ovary

Abstract

It has been suggested that locally-produced insulin-like growth factor binding protein 4 (IGFBP4) inhibits ovarian follicular growth and ovulation by interfering with IGF action. According to this hypothesis, IGFBP4-expressing follicles should demonstrate atresia while healthy dominant follicles should be devoid of IGFBP4. Alternatively, according to this view, there could be constitutive expression of the inhibitory IGFBP4 but selective expression of an IGFBP4 protease in dominant follicles, allowing the follicle to mature and ovulate due to degradation of the binding protein. To examine these views on IGFBP4's role in primate follicular selection, we analyzed cellular patterns of IGFs 1 & 2, IGFBP4 and the IGFBP4 protease (PAPP-A) mRNA expression in ovaries from late follicular phase rhesus monkeys using in situ hybridization. IGF1 mRNA was not detected but IGF2 mRNA was abundant in theca interna and externa of all antral follicles, and was present in the granulosa of large pre-ovulatory and ovulatory follicles. IGFBP4 mRNA was selectively expressed by LH receptor (LHR) mRNA-positive theca interna cells of healthy antral follicles (defined by aromatase and gonadotropin receptor expression), and by LHR-expressing granulosa cells found only in large pre-ovulatory and ovulatory follicles (defined by size and aromatase expression). PAPP-A mRNA was abundant in granulosa cells of most follicles without obvious relation to IGFBP4 expression. Ovarian IGFBP4 mRNA levels were markedly increased after treatment with the LH analog, human chorionic gonadotropin (hCG), while IGF2 and PAPP-A mRNAs were not significantly altered. In summary, IGFBP4 expression appears to be associated with follicular selection, not atresia in the monkey ovary. IGFBP4 is consistently expressed in healthy theca interna and in luteinized granulosa cells, likely under LH regulation. The IGFBP4 protease, PAPP-A is widely expressed without apparent selectivity for IGFBP4-expressing follicles or for dominant follicles. These observations suggest that IGFBP4 or an IGFBP4 proteolytic product may be involved with LH-induced steroidogenesis and/or luteinization rather than inhibition of follicular growth.