Effects of antiprogesterone on pregnancy: I. Midpregnancy

Abstract

Isoxazole is a synthetic steroid of the family of androstano[2,3-d] isoxazoles. It is an antiprogesterone (A-P), since by inhibiting the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSDH), it blocks the conversion of pregnenolone to progesterone (P). The antifertility and in vivo mechanism of action of this A-P were studied in 130 rats in midpregnancy. The animals were treated on day 10 of pregnancy with a single oral dose of vehicle (41 controls) or 1.25 to 10 mg. of isoxazole (58 rats), or 10 mg. of isoxazole plus 5 mg. of P intramuscularly (31 rats). Subsequently, sampling was done once on days 10 through 14 of pregnancy. The samples collected were: (1) sets of conceptuses, (2) the tail vein blood, (3) the uterine vein blood, and (4) uterine tissue. The weights of 1,370 conceptuses were measured, and in 260 plasma and 130 tissue samples the concentrations of : (1) P, (2) estradiol-17β, and (3) prostaglandin F (PGF) were determined by radioimmunoassays. The minimum antifertility dose of isoxazole was 2.5 mg. per rat (9 mg. per kilogram of body weight), while a dose of 1.25 mg. was ineffective. Effective isoxazole treatment provoked fetal death in utero by 12 hours and spotting and significant reduction (P < 0.001) in conceptus weight within 24 hours. These effects of isoxazole on pregnancy were provoked within 12 hours by a highly significant decrease of P in tail and uterine vein plasma and uterine tissue (P < 0.001) and by an increase in PGF in uterine tissue (P < 0.001) and uterine vein plasma (P < 0.01). The conclusion that the antifertility action of isoxazole resulted from a regulatory imbalance triggered by P withdrawal (Pw), rather than from a direct effect of isoxazole on the fetus, was based on the finding that when the A-P-induced Pw was prevented by P substitution, pregnancy continued normally. The academic and potential therapeutic significance of these observations is discussed.