Adult female rats were treated for 2 or 4 weeks with the progesterone antagonist RU486 to study its effect on the regulation of ovarian function. In rats with 5-day ovarian cycles, the vaginal cyclicity disappeared. Uninterrupted vaginal cornification emerged within 4 days after the start of treatment and cornification persisted for the whole period of treatment. It took more than 2 weeks after cessation of 2-4 weeks of treatment before 5-day vaginal cycles reappeared. Ovarian weights increased rapidly resulting from the accumulation of large numbers of corpora lutea. In addition, the ovaries developed occasional follicular cysts which could reach an extremely large size (2 mm or more). Analysis of serial histological sections of ovaries, combined with plasma concentrations of estradiol-17 beta and progesterone, indicated cyclic ovulation and corpus luteum formation together with persistence of functional activity of already existing and newly formed corpora lutea. RU486 seems to have the unique property of dissociating cessation of luteal activity and ovulation in rats. After treatment with RU486, pituitary enlargement and mammary gland alveolar development were observed. It is hypothesized that these effects result from unopposed estrogen action on PRL secretion. The effects of RU486 are reversible: 4 to 5 weeks after the end of treatment ovarian activity seems normal (as evidenced by reduction of ovarian weights and 5-day vaginal cycles) except for the presence of occasional large follicular cysts which may require longer periods for their regression.

combined treatment (antiprogestin plus antiestrogen or LHRH-agonist) may be of value in endocrine therapy of breast cancer.

No abstract

Tumour Leydig cells have been incubated in the presence or absence of lutropin (luteinizing hormone, ;LH'). Stimulation of cells with lutropin (1000ng/ml) in the presence of 1-methyl-3-isobutylxanthine (0.25mm) resulted in increased steroid production and increased protein phosphorylation. When pregnenolone metabolism was inhibited, basal pregnenolone production was 26.9+/-7.4ng/60min per 10(6) cells; stimulated production was 156.1+/-39.5ng/60min per 10(6) cells (means+/-s.d., n=4). Lutropin-dependent phosphorylated proteins of molecular mass 17000, 22000, 24000, 33000 and 57000Da were detected. A significant increase of [(32)P]P(i) incorporation into these phosphorylated proteins was observed concomitant with the increased pregnenolone production. The occurrence of the phosphoproteins in nuclei, mitochondria and postmitochondrial-supernatant was investigated. The 17000Da phosphoprotein was found in the nuclear fraction, whereas the 22000, 24000, 33000 and 57000Da phosphoproteins were localized in the postmitochondrial-supernatant fraction. Of the cholesterol-side-chain-cleavage activity, 80.3+/-6.1% (mean+/-s.d., n=5) was present in the mitochondrial fraction isolated from tumour Leydig cells, and this activity was 2.5-fold increased when cells had been preincubated with lutropin/1-methyl-3-isobutylxanthine (basal production: 194.6+/-28.6ng/30min per mg of protein; lutropinstimulated production: 498.8+/-91.5ng/30min per mg of protein; means+/-s.d., n=3). The similarities in the kinetics of the phosphorylation of proteins and the pregnenolone production after addition of lutropin/1-methyl-3-isobutylxanthine indicate that the phosphoproteins could be involved in the lutropin-dependent increase in steroidogenesis in tumour Leydig cells. It remains to be demonstrated, however, to what extent the phosphoproteins outside the mitochondria can influence the cholesterol-side-chain-cleavage activity inside the mitochondria.