Ovarian effects of an anti-inflammatory-immunomodulatory drug in the rat.
The purpose of this study was to determine whether a 30-day administration of SK&F 86002-A2, an inhibitor of cyclooxygenase and 5-lipoxygenase pathways of arachidonate metabolism, adversely affected reproductive cycles, ovarian structure, and/or pituitary/ovarian hormone secretion. Cyclooxygenase and 5-lipoxygenase enzymes catalyze the reactions leading to the synthesis of prostaglandins and leukotrienes, respectively, which are physiological regulators of ovarian function. Female rats were dosed once daily by gavage with 0, 1, 5, 10, 30, or 60 mg (base)/kg/day of SK&F 86002-A2 for 30 consecutive doses beginning on the day of vaginal proestrus. Vaginal smears were then examined daily until necropsy, when ovaries and uteri were collected for macroscopic and histological examination. In addition, serum concentrations of estradiol, progesterone, luteinizing hormone, follicle stimulating hormone, and prolactin were estimated by radioimmunoassay. Estrous cycle irregularity, resulting from a dose-related lengthening of the interestrous interval, significantly (p less than 0.05) reduced the number of cycles in rats receiving 60 mg/kg/day of SK&F 86002-A2 compared to controls. Furthermore, the ovaries from this group of rats weighed significantly more (p less than 0.05) than controls, apparently due to an increased occurrence of enlarged, cystic follicles that occasionally contained blood. Luteinized follicles with entrapped ova were also detected during histological examination. Dilatation of the uterine lumen was observed in some rats receiving doses of SK&F 86002-A2 greater than 1 mg/kg/day. Serum progesterone in rats receiving 60 mg/kg/day of SK&F 86002-A2 was significantly (p less than 0.05) lower than controls. In contrast, mean levels of serum estradiol were elevated in rats receiving 30 mg/kg/day of SK&F 86002-A2. Serum concentrations of FSH, LH, and prolactin were not significantly different in any group. The results of this study suggest that SK&F 86002-A2 disrupts cyclic ovarian function by a local, cumulative action that inhibits ovulation and alters steroid secretion.
Walker
R F
RF
Department of Reproductive and Developmental Toxicology, Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101.
Schwartz
L W
LW
Manson
J M
JM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004971:Estrus / Q000187:drug effects; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood; D007093:Imidazoles / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects*; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012739:Gonadal Steroid Hormones; D007093:Imidazoles; D013844:Thiazoles; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole