In vivo Effects of Estetrol on the Immature Rat Uterus

Abstract

The estrogenic activity of 1,3,5(10)-estratriene-3, 15α, 16α, 17β-tetrol (estetrol, E4), a major metabolite of placental estrogens in the human fetus, was evaluated by examination of uterine responses to s.c. administration of the compound to immature rats in two different doses, 10 and 50 µg/100 g bw. The effects were compared with those obtained by administration of 1 µg/100 g bw of either estradiol (E2) or estriol (E3). Responses were determined at 6, 24 and 36 h after one injection or at 48 h after 2 injections, given at 0 and 24 h. The parameters measured were: uterine wet weight, luminal fluid weight, alkaline phosphatase activity, DNA and protein content. Estetrol, at the 2 levels tested, induced an elevation in uterine weight, measured after removal of luminal fluid, and an accumulation of luminal fluid as noted 6 h after injection. A similar effect was obtained with E2. Uterine wet weight and luminal fluid volume returned to control level by 24 h after E4 administration, whereas both remained elevated after E2 injection. After 2 injections, all compounds induced uterine wet weight increases, but E4, in either dose, failed to raise the luminal fluid volume. Estetrol increased protein content only after 2 daily injections at both the 10 and 50 µg levels. No change in protein content was noted 24 h after the first injection. In contrast, E2 at 1/50 the dose of E4 augmented uterine protein at 24 h and produced a much greater effect than E4 after 2 injections. Injection of 50 µg E4 together with 1 µg E2 did not alter the effect obtained with this dose of E2 alone. No changes in the specific activity of alkaline phosphatase were observed. This enzymatic activity cannot be considered to be specifically induced by estrogens, although it serves as a convenient marker to evaluate changes in uterine protein content, In contrast to the effect of E2, estetrol did not significantly increase the DNA content per uterus at any of the dosage schedules tested. No statistically significant differences were noted between the effects of E3 and E4 on any parameter tested at the levels of 1 and 50 µg/100 g bw, respectively. However, uterine wet weight, luminal fluid and protein or DNA content were smaller after 10 µg/100 g bw of E4 than after E3. It is concluded that E4, administered as a single dose or in 2 doses at a 24 h interval is a weak estrogen which produces effects of short duration. It cannot, however, be considered entirely devoid of estrogenic activity, even though true uterine hyperplasia, as estimated by DNA content, was not promoted by administration of the two 50 µg/100 g bw doses of estetrol.