In vivo Effects of Estetrol on the Immature Rat Uterus

• Published in: Biology of reproduction Vol. 20; no. 2; pp. 242 - 246
• Main Authors: Holinka, C F, Gurpide, E
• Format: Journal Article
• Language: English
• Published: United States Society for the Study of Reproduction 01-03-1979
• Subjects: Alkaline Phosphatase - metabolism; Animals; DNA - metabolism; Dose-Response Relationship, Drug; Estetrol - pharmacology; Estradiol - pharmacology; Estriol - analogs & derivatives; Extracellular Space - metabolism; Female; Organ Size - drug effects; Proteins - metabolism; Rats; Time Factors; Uterus - drug effects; Uterus - metabolism
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1093/biolreprod/20.2.242

The estrogenic activity of 1,3,5(10)-estratriene-3, 15α, 16α, 17β-tetrol (estetrol, E 4 ), 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 (E 2 ) or estriol (E 3 ). 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 E 2 . Uterine wet weight and luminal fluid volume returned to control level by 24 h after E 4
administration, whereas both remained elevated after E 2 injection. After 2 injections, all compounds
induced uterine wet weight increases, but E 4 , 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, E 2 at 1/50 the
dose of E 4 augmented uterine protein at 24 h and produced a much greater effect than E 4 after 2
injections. Injection of 50 µg E 4 together with 1 µg E 2 did not alter the effect obtained with this
dose of E 2 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 E 2 , 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 E 3 and E 4 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 E 4 than after E 3 .
It is concluded that E 4 , 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.