Impaired estrogen action in the uterus of insulin-like growth factor binding protein-1 transgenic mice.

Insulin-like growth factor-I (IGF-I) has been implicated as autocrine/paracrine mediator of estrogen action in the rodent uterus. Here, we examined the effects of 17-beta estradiol (E2), epidermal growth factor (EGF), and IGF-I on DNA synthesis in the uterus of ovariectomized (ovex) transgenic mice (Tg), which overexpress rat insulin-like growth factor binding protein-1 (IGFBP-1). Litter size was significantly reduced in Tg mice compared with wild-type mice. Immunohistochemical studies localized the expression of the transgene to the luminal and glandular epithelium. In addition, rat IGFBP-1 immunoreactivity was present in luminal secretions. E2-induced uterine DNA synthesis as measured by methyl-3H thymidine incorporation, was significantly reduced in ovex Tg mice; 4.77 +/- 0.59 and 4.97 +/- 0.53 for Tg strains 57C and 277A, respectively, compared with 8.65 +/- 0.73 fmol/microgram of DNA for Wt mice. Similarly, uterine weight after three daily injections of E2 was reduced in Tg mice compared with Wt mice; 2.85 +/- 0.39 vs. 4.23 +/- 0.26 mg/g BW, P < 0.01. Semiquantitative RT-PCR assays were used to demonstrate changes in uterine IGF-I messenger RNA (mRNA) and EGF mRNA abundance after administration of E2. An approximately 3-fold increase in IGF-I mRNA abundance was seen 6 h after E2 in both Tg and Wt mice. Over the same time course, little change was seen in EGF mRNA levels, which were similar in Tg and Wt mice. After 3 days of E2 treatment, an increase in EGF mRNA was apparent in Wt mice but not in Tg mice. The uterine DNA response to both IGF-I and EGF was significantly attenuated in Tg mice compared with Wt mice. The data reported here together with previous reports of E2 regulation of IGF-I and IGFBP-1 expression in uterus support the hypothesis that the IGF-I is a mediator of estrogen action in the uterus. In addition attenuation of the EGF response in the uterine tissue of Tg mice suggests that this response is also mediated, in part, by IGF-I.