The selective estrogen receptor modulator, raloxifene: reproductive assessments following premating exposure in female rats.
Raloxifene HCl is a nonsteroidal, selective estrogen receptor modulator developed as a therapeutic agent for postmenopausal osteoporosis. Two studies were conducted that examined the effects of premating exposure to raloxifene HCl. In the first study, adult female CD rats (20/group) were given diets containing 0, 0.01, or 0.1% raloxifene (providing an average of 0, 6, or 63 mg/kg/d, respectively) for 2 weeks, after which the treated diets were replaced with control diet. Following a 2-week period without treatment, each female that had displayed at least three conversions in vaginal cytology from cornified cells to leukocytes was cohabited for 1 to 2 d with an untreated male as she entered proestrus. Females were killed at midgestation and examined for evidence of pregnancy. In the second study, adult female CD rats (40/group) were given oral gavage doses of raloxifene (0, 0.1, 1, or 10 mg/kg/d) for 4 weeks. Immediately or following a 2-week period without treatment, 20 females/group were cohabited with untreated males (1:1) for up to 3 weeks. The females were allowed to deliver and rear their offspring until Postpartum Day 21. Progeny survival, growth, and development were evaluated. Maternal body weight, body weight gain, and food consumption were depressed in all raloxifene treatment groups. Doses > or =1 mg/kg caused disruptions in estrous cycles. In Study 1, 90% of the females treated with raloxifene resumed normal cycling, and fertility was not significantly affected. Although there were no statistically significant differences in time-to-mating, fertility, or liveborn indices in Study 2, females in the 10-mg/kg immediate-cohabitation group had slightly increased gestation lengths and smaller litter sizes. Progeny from these litters were larger on Postpartum Day 1 and had advanced incisor eruption and eye opening. In addition, slight delays were seen in physical landmark appearance in the 0.1- and 1-mg/kg immediate-cohabitation groups and in the 1- and 10-mg/kg delayed-cohabitation groups. Progeny viability, growth, and negative geotactic performance were not adversely affected. In these studies of maternal premating exposure to raloxifene, findings were consistent with established pharmacologic activity of the test chemical. Reproductive effects (disrupted estrous cycles and decreased litter size) occurred at doses > or =1 mg/kg and were generally reversible. Effects on offspring were seen at doses > or =0.1 mg/kg, were of minor importance, and were resolved during the lactation period.
Hoyt
J A
JA
Toxicology and Drug Disposition, Lilly Research Laboratories, A Division of Eli Lilly and Company, Greenfield, Indiana 46140, USA. J.A.Hoyt@Lilly.com
Fisher
L F
LF
Buelke-Sam
J L
JL
Francis
P C
PC
D000704:Analysis of Variance; D000818:Animals; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004971:Estrus / Q000187:drug effects*; D005069:Evaluation Studies as Topic; D005260:Female; D005865:Gestational Age; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011247:Pregnancy; D020849:Raloxifene Hydrochloride; D051381:Rats; D011960:Receptors, Estrogen / Q000819:agonists / Q000187:drug effects*; D012098:Reproduction / Q000187:drug effects*; D012726:Sexual Behavior, Animal
D004965:Estrogen Antagonists; D010880:Piperidines; D011960:Receptors, Estrogen; D020849:Raloxifene Hydrochloride