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 primat e myometrium and are implicated in the sex steroid-induced growth of t his tissue. To evaluate the potential for modulation of IGF action in the primate myometrium by locally produced IGF binding proteins (IGFBP s), we examined the cellular localization and sex steroid regulation o f IGFBPs 1-5 in the nonhuman primate uterus. Ovariectomized rhesus mon keys were treated with placebo, estradiol (E(2)), or E(2) and progeste rone (P-4) (E(2) and P-4) for 2 weeks, after which their uteri were re moved and cut into thin serial sections for analysis by in situ hybrid ization. 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 expres sed by myometrial smooth muscle cells but each displayed distinctive p atterns of regulation by sex steroids. IGFBP-2 was barely detectable i n control myometrium, was significantly increased by E, and even more significantly by E(2) and P-4. IGFBP-4 and 5 mRNAs were readily detect able in control myometrium and significantly increased by E(2) treatme nt. The addition of P-4 to E(2) treatment did not produce a significan tly 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 co ntrast to other IGFBPs was significantly reduced by approximately 75% in smooth muscle cells by E(2) and by E(2) and P-4 treatment. Interest ingly, however, IGFBP-3 mRNA was increased in the uterine vascular end othelium 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 t he primate myometrium, and that their expression is differentially reg ulated by sex steroids. The cellular and sex steroid-regulated pattern of IGFBP-2 gene expression is very similar to that of IGF-I, as previ ously determined in these same myometrial samples. Both IGF I and IGFB P-2 are dependent on E(2) for significant myometrial expression, and b oth are further augmented by the addition of P-4 to E(2) treatment. Ut erine smooth muscle IGFBP-3 mRNA levels are negatively regulated, wher eas 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. Th e present observations, together with our previous data from the same animals, demonstrate that the primate myometrial smooth muscle cell ex presses mRNAs for IGF-I and -II, IGF-I and -II receptors, as well as e xpresses mRNAs for IGFBP-2, -3, -4, and -5. These data provide evidenc e for complex local interactions between IGF system components regulat ed by estrogen and progesterone.