Effect of estrogen inhibitors on conceptus estrogen synthesis and development in the gilt

Two estrogen antagonists (keoxifene and clomiphene) and two aromatase inhibitors (LY56110 and 4-hydroxyandrostenedione, 4-OHA) were utilized to determine the role of conceptus estrogen in trophoblastic elongation and maintenance of pregnancy in the pig. Pregnant gilts were unilaterally hysterectomized on day 10.5, and infused via a uterine arterial catheter with 200 mg of keoxifene or vehicle. The remaining uterine horn was removed based on time estimated for conceptus elongation. In a second study, pregnant gilts were injected daily with 200 mg (i.m.) of clomiphene or vehicle during pregnancy (days 10-16) and hysterectomized on day 30. A third study assessed in vitro aromatase inhibition by 4-OHA and LY56110 using trophoblastic microsomes incubated with [1 beta, 2 beta-3H]-androstenedione for 6 hr. In a fourth study, in vivo inhibition of aromatase activity was determined. For this study pregnant gilts, unilaterally hysterectomized on day 10.5, received either 4-OHA, LY56110, or vehicle. Conceptus development and uterine estrogens were quantified. None of the estrogen antagonists and aromatase inhibitors interferred with conceptus elongation. Uterine protein, calcium and Acid Phosphatase were similar (P greater than .10) between keoxifene- and vehicle-treated gilts. Embryonic survival of clomiphene- and vehicle-treated gilts was similar (91.5 vs 87.4%). In vitro, 4-OHA and LY56110 had 50% inhibitory concentrations of 0.1 microM and 13 nM. Treatment of gilts with 4-OHA reduced total estrogens in uterine flushings by 57% (P less than .02), whereas treatment with LY56110 did not significantly lower total estrogen content in uterine flushings. Estrogen antagonists were not effective in blocking conceptus elongation and maintenance of pregnancy. Although estrogen synthesis can be inhibited in vitro, dosages of aromatase inhibitors used were not totally effective in vivo.