Reduced estradiol production by a substituted triazole results in delayed ovulation in rats.
Ovulation in the rat is delayed by a single administration of the substituted triazole R151885 (1,1-di(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-ethanol). This delay results from a 24-hr shift in the preovulatory luteinizing hormone (LH) surge since administration of chorionic gonadotrophin on proestrus restores ovulation. Plasma levels of estradiol are markedly reduced (42-45%) 6-12 hr after administration of R151885. The restoration of ovulation in R151885-pretreated rats, by administration of exogenous estradiol benzoate, indicates that the reduced estradiol levels play a pivotal role in the delay of ovulation. Granulosa cells isolated from rat ovaries produce estradiol and progesterone in vitro in the presence of both follicle-stimulating hormone and testosterone. The addition of R151885 to such cultures results in a dose-dependent inhibition of estradiol production (69% by 1 microM) without a significant effect on progesterone production. This inhibition occurs at concentrations of R151885 similar to those measured in vivo. R151885 is a competitive inhibitor of human placental aromatase (apparent Ki with androstenedione substrate of 410 nM) and produces a type II spectral perturbation of cytochrome P-450 from placental microsomes. Pituitaries isolated from R151885-treated rats have reduced LH output in response to gonadotrophin-releasing hormone stimulation compared with those of controls. It is proposed that R151885 competitively inhibits aromatase activity in developing ovarian follicles. The resultant temporary reduction of plasma estradiol levels at a critical time in the estrous cycle, and consequent inadequate pituitary sensitization, produces a 24-hr delay in the preovulatory LH surge and hence ovulation is delayed by 24 hr.
Milne
C M
CM
Central Toxicology Laboratory, Imperial Chemical Industries PLC, Macclesfield, United Kingdom.
Hasmall
R L
RL
Russell
A
A
Watson
S C
SC
Vaughan
Z
Z
Middleton
M C
MC
D000818:Animals; D047072:Aromatase Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004958:Estradiol / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007986:Luteinizing Hormone / Q000097:blood; D010060:Ovulation / Q000187:drug effects*; D010906:Pituitary Hormone-Releasing Hormones / Q000494:pharmacology; D011374:Progesterone / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D010906:Pituitary Hormone-Releasing Hormones; D014230:Triazoles; D011374:Progesterone; D004958:Estradiol; C048318:R 151885; D007986:Luteinizing Hormone; D003577:Cytochrome P-450 Enzyme System