Sex steroid regulation of insulin-like growth factor system gene expression and proliferation in primate myometrium

To investigate the role of locally produced insulin-like growth factors (IGFs) in sex steroid-induced growth in the primate uterus, ovariectomized rhesus monkeys were treated with placebo (control), estradiol (E(2)) alone, or E(2) plus progesterone (P-4). After 2 weeks, uteri were removed, and serial thin uterine sections were analyzed by in situ hybridization for IGF-I, IGF-II, and IGF-I and -II receptor messenger ribonucleic acids (mRNAs) and by immunocytochemistry for the cell proliferation-specific antigen Ki-67. IGF-I and IGF-II and both IGF receptor mRNAs are coexpressed by smooth muscle cells, supporting the possibility of autocrine/paracrine IGF action in stimulating myometrial growth. IGF-I mRNA is barely detected in control myometrium, is significantly increased by E(2) treatment, and is augmented even more by the combination of E(2) and P-4 treatment, whereas little change is noted in myometrial IGF-II or IGF-I receptor mRNA levels. Ki-67-positive myometrial nuclei are also significantly increased by E(2) and are augmented even more by E(4) plus P-4 treatment, with a correlation between local IGF-I mRNA concentration and local Ki-67-positive cell count of r = 0.891 (P = 0.003). These data provide direct experimental evidence for regulation of IGF-I gene expression by sex steroids in the primate uterus in vivo and implicate local IGF-I action in both estrogen- and P-4-induced myometrial growth.