The antiovulatory effect of the antiprogestin onapristone could be related to down-regulation of intraovarian progesterone (receptors).
The present study was undertaken to investigate intraovarian mechanism(s) for the antiovulatory effect of Onapristone (ON), because antiprogestins possessing the same antiprogestational activity and inhibiting the preovulatory LH surge to the same extent differ in their antiovulatory potency. Ovulation was induced by treating immature female rats with pregnant mare serum gonadotropin (PMSG) for folliculogenesis and hCG for the induction of ovulation. The animals were treated twice with ON (200 mg/kg 42 h and 48 h after PMSG) and killed at different times. The ovulation rate was assessed by counting the number of ova in the fallopian tubes and uteri. Blood and ovaries were collected for radioimmunoassay (RIA) of steroid hormones and histological analysis for 3beta-hydroxysteroid dehydrogenase (3beta-HSDH), 17beta-hydroxysteroid dehydrogenase (17beta-HSDH), progesterone (PR), estrogen (ER) and androgen (AR) receptors. Treatment with ON totally blocked ovulation and the progesterone (P4) surge was significantly diminished in comparison to the control (6-8 h post-hCG), whereas androgen levels remained unaffected. The decreased P4 concentrations correlated well with a reduced staining intensity of 3beta-HSDH in granulosa cells of tertiary follicles. Moreover, we observed a down-regulation of PR in granulosa cells of tertiary follicles. Additionally, in secondary and tertiary follicles the expression of AR between 0 and 6 h after hCG was reduced. These results suggest that the antiovulatory effect of the antiprogestin ON is related to down-regulation of intraovarian progesterone, caused by attenuated 3beta-HSDH activity and PR expression. One can thus assume that intraovarian P4 is an important factor for the induction of ovulation. An effect of ON on the staining intensity of 17beta-HSDH in theca and granulosa cells could not be observed at any time. In conclusion, the inhibition of ovulation induced by the antiprogestin, ON, could be related to decreased intraovarian progesterone production through reduced 3beta-HSDH activity and the down-regulation of PR.
Donath
J
J
Research Laboratories of Schering AG, Berlin, Germany.
Michna
H
H
Nishino
Y
Y
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000735:Androstenedione / Q000097:blood / Q000378:metabolism; D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004958:Estradiol / Q000097:blood / Q000378:metabolism; D005260:Female; D006064:Gonadotropins, Equine / Q000494:pharmacology; D006067:Gonanes / Q000494:pharmacology*; D006107:Granulosa Cells / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D007700:Kinetics; D010053:Ovary / Q000187:drug effects / Q000502:physiology*; D010060:Ovulation / Q000187:drug effects*; D010062:Ovulation Induction; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D013799:Theca Cells / Q000378:metabolism
D006063:Chorionic Gonadotropin; D006064:Gonadotropins, Equine; D006067:Gonanes; D006727:Hormone Antagonists; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000735:Androstenedione; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; C053238:onapristone