Search

The clinical phenotype of complete androgen insensitivity (CAIS) was associated with a mutation in the human androgen receptor (hAR) gene encoding the amino acid substitution, M745I, in the hAR protein. Transcriptional activation of hAR(M745I) by the synthetic androgen, methyltrienolone (R1881), was reduced compared to wild-type (wt) hAR. The transcriptional co-activator, androgen receptor associated protein 70 (ARA70), failed to enhance transactivation of hAR(M745I) at lower concentrations of R1881 (0.01–0.1 nM), whereas the p160 co-activators, SRC-1 and TIF2, stimulated activity. Transcriptional activity of hAR(M745I) was stimulated by 1 or 10 nM R1881 and activity was further enhanced by co-expression of ARA70 similar to that of the hAR(wt). Transcriptional activity of hAR(wt) was minimally stimulated by estradiol (E2) without or with co-expression of ARA70, whereas 10 or 100 nM E2 increased transactivation by hAR(M745I) of the androgen-responsive MMTV-luciferase reporter gene by 10-fold and activity was further enhanced by ARA70. Increasing concentrations of E2 competed more effectively for binding of R1881 to hAR(M745I) than to hAR(wt), indicative of the preferential binding of E2 to the mutant hAR. Partial tryptic digestion of hAR wt and M745I revealed that activation of the mutant protein was reduced in the presence of R1881. By contrast, tryptic digestion showed that the mutant hAR was activated by the binding of E2. In conclusion, the clinical phenotype of CAIS resulted from a hAR gene mutation encoding hAR(M745I) with reduced binding and transactivation by androgens, but the novel properties of enhanced affinity for and increased transactivation by estradiol.

The present study determined whether estrogen plays a role in regulating invasion and remodeling of the uterine spiral arteries by extravillous trophoblasts during early baboon pregnancy. The level of trophoblast invasion of spiral arteries was assessed on day 60 of gestation (term is 184 days) in baboons untreated or treated on days 25-59 with estradiol or aromatizable androstenedione. The administration of estradiol or androstenedione increased (P0.01) maternal serum estradiol levels approximately 3-fold above normal. The mean+/-SE percentage of spiral arteries/arterioles invaded by extravillous cytotrophoblasts in estradiol-treated baboons for vessels with diameters of 26-50 microm (0.0+/-0.0), 51-100 microm (1.2+/-0.7) and100 microm (13.2+/-5.5) was 100%, 90%, and 75% lower (P0.001), respectively, than in untreated baboons (2.4+/-1.2%; 11.0+/-5.5%, and 54.5+/-8.5%, respectively). Similar results were obtained with androstenedione treatment. However, the distribution of uterine spiral arteries grouped by diameter or number of arteries per basal plate area, i.e. microvessel density, were similar in untreated and estrogen-treated baboons. We suggest, therefore, that the low levels of estrogen exhibited during early primate pregnancy are required to permit normal progression of trophoblast vascular invasion and that the surge in estrogen which occurs during the second-third of normal pregnancy has a physiological role in suppressing further arterial trophoblast invasion. Consequently, we propose that the estrogen-dependent restraint of spiral artery invasion/remodeling ensures optimal blood flow dynamics across the uteroplacental vascular bed to promote normal fetal growth and development.