Cellular localization and sex steroid regulation of insulin-like growth factor binding protein messenger ribonucleic acids in the primate myometrium.

Insulin-like growth factors (IGF)-I and -II are abundant in the primate myometrium and are implicated in the sex steroid-induced growth of this tissue. To evaluate the potential for modulation of IGF action in the primate myometrium by locally produced IGF binding proteins (IGFBPs), we examined the cellular localization and sex steroid regulation of IGFBPs 1-5 in the nonhuman primate uterus. Ovariectomized rhesus monkeys were treated with placebo, estradiol (E(2)), or E(2) and progesterone (P-4) (E(2) and P-4) for 2 weeks, after which their uteri were removed and cut into thin serial sections for analysis by in situ hybridization. IGFBP-1 messenger RNA (mRNA) was not detected in control or E(2)-treated uteri but was found in a few unidentified cells in the E(2) and P-4-treated group. IGFBP-2, -3, -4, and -5 mRNAs were all expressed by myometrial smooth muscle cells but each displayed distinctive patterns of regulation by sex steroids. IGFBP-2 was barely detectable in control myometrium, was significantly increased by E, and even more significantly by E(2) and P-4. IGFBP-4 and 5 mRNAs were readily detectable in control myometrium and significantly increased by E(2) treatment. The addition of P-4 to E(2) treatment did not produce a significantly greater augmentation in IGFBP-4 or 5 mRNA level compared with E(2) alone. IGFBP-3 mRNA was abundant in the control myometrium, but in contrast to other IGFBPs was significantly reduced by approximately 75% in smooth muscle cells by E(2) and by E(2) and P-4 treatment. Interestingly, however, IGFBP-3 mRNA was increased in the uterine vascular endothelium by E(2) and by E(2) and P-4 treatment. In summary, this study has shown that four of the six known IGFBPs are highly expressed in the primate myometrium, and that their expression is differentially regulated by sex steroids. The cellular and sex steroid-regulated pattern of IGFBP-2 gene expression is very similar to that of IGF-I, as previously determined in these same myometrial samples. Both IGF I and IGFBP-2 are dependent on E(2) for significant myometrial expression, and both are further augmented by the addition of P-4 to E(2) treatment. Uterine smooth muscle IGFBP-3 mRNA levels are negatively regulated, whereas IGFBP-4 and -5 mRNA levels are positively regulated by E(2); none of these myometrial IGFBPs appears sensitive to the effects of P-4. The present observations, together with our previous data from the same animals, demonstrate that the primate myometrial smooth muscle cell expresses mRNAs for IGF-I and -II, IGF-I and -II receptors, as well as expresses mRNAs for IGFBP-2, -3, -4, and -5. These data provide evidence for complex local interactions between IGF system components regulated by estrogen and progesterone.