Ovarian effects of SK&F 86002-A2 in the rat: site of action.
In a preliminary 30-day study, oral administration of SK&F 86002-A2, an inhibitor of prostaglandin and leukotriene synthesis, blocked ovulation and altered ovarian structure and hormone production in rats. The purpose of the present study was to determine if the locus of action of SK&F 86002-A2 for these effects was the ovary or some other site in the female reproductive system, using a number of experimental approaches. A single sc or intraovarian injection of SK&F 86002-A2 did not block spontaneous or gonadotropin-induced ovulation in proestrous rats, whereas indomethacin, a positive control, acutely disrupted the ovulatory process. Since neither route of administration blocked ovulation, integrated pituitary and ovarian events were not negatively affected by a single injection of SK&F 86002-A2 at doses which caused ovarian dysfunction when administered repeatedly for 30 days. In contrast to a single dose, oral administration of SK&F 86002-A2 to hypophysectomized rats for 2 weeks suppressed follicular growth and estradiol production in response to sc administration of pregnant mare serum gonadotropin. Although ovarian function was suppressed in hypophysectomized rats, LH surges induced by estradiol in ovariectomized rats were not affected by administration of SK&F 86002-A2 for 2 weeks. Thus, hypothalamic/pituitary dysfunction did not contribute to the ovarian effects of SK&F 86002 that occurred after repeated dosing. In conclusion, these results indicate that disruption of ovarian cycles by SK&F 86002-A2 is related to a direct effect on the ovary, and not to altered hypothalamic/pituitary function and LH release. Specifically, SK&F 86002-A2 may suppress the ovarian response to gonadotrophin, retarding follicular growth and estrogen production. The ovarian effects are consistent with a pharmacological expression of the inhibitory action of SK&F 86002-A2 on prostaglandin and leukotriene synthesis.
Walker
R F
RF
Department of Reproductive and Developmental Toxicology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
Schwartz
L W
LW
Torphy
T J
TJ
Newton
J F
JF
Manson
J M
JM
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007016:Hypophysectomy; D007093:Imidazoles / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007986:Luteinizing Hormone / Q000097:blood; D006080:Ovarian Follicle / Q000187:drug effects; D010053:Ovary / Q000187:drug effects*; D010060:Ovulation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D013844:Thiazoles; D004958:Estradiol; D007986:Luteinizing Hormone; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole