Elevated luteal phase estradiol:progesterone ratio in mice causes implantation failure by creating a uterine environment that suppresses embryonic metabolism.

Failure of implantation after in vitro fertilization is sometimes associated with elevated estradiol (E2):progesterone (P) ratios in the early luteal phase. Using the mouse to study the causes of the contragestational actions of elevated E2:P ratios, it was confirmed that administration of E2 (40 to 80 ng) before implantation inhibited implantation and 0.4 mg of P totally reversed the effect of 40 ng E2. Fluids collected from the uterine lumen of E2-treated (40 ng) mice significantly inhibited the incorporation of 3H-uridine by mouse blastocysts in vitro, whereas fluids from mice treated with E2 (40 ng) and P (0.4 mg) together had no inhibitory effect. In contrast to these contraceptive effects of high E2, lower levels of E2 (5 and 20 ng) caused an increase and no change to the implantation rate, respectively, and fluids from mice treated with E2 (20 ng) significantly enhanced blastocyst metabolism. Concomitant administration of P to these low dose E2 mice enhanced these effects. Thus, a large elevation of the E2:P ratio inhibited implantation and created a uterine lumenal milieu that suppressed embryonic metabolism. These effects could be reversed and implantation re-established by the correction of the E2:P ratio by exogenous P.