The reversible effects of raloxifene on luteinizing hormone levels and ovarian morphology in mice.
Raloxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and serum lipids and estrogen antagonist effects on breast and uterine tissues. This study assessed the effects of raloxifene hydrochloride (HCl) treatment on circulating luteinizing hormone (LH) levels and ovarian morphology in sexually mature, 15-week-old, female CD-1 mice. Mice were maintained on diets providing average daily doses of 0 or 233 mg/kg raloxifene for 2 weeks (Study 1) or 0, 7.9, or 236 mg/kg raloxifene for 4 weeks (Study 2). At the end of the treatment period, blood samples were collected every 2 hours for 24 h in Study 1 (5 mice per group) and at 10:00 a.m. and 10:00 p.m. in Study 2 (8 mice per group). Serum LH levels were measured by radioimmunoassay. Ovarian histomorphology was evaluated in the 10 mice per group (Study 1) and the 8 mice per group (Study 2). For the reversibility phase (Study 2), mice were fed untreated diets for 3 weeks; serum LH levels and ovarian histomorphology were then assessed. Raloxifene treatment at 233 mg/kg/day for 2 weeks (Study 1) significantly elevated circulating LH levels by 4- to 7-fold compared with control. Raloxifene-treated mice had elevated LH levels sustained over the 24-h sampling period and did not exhibit the preovulatory LH surge evident in some control mice at the 4:00 p.m., 6:00 p.m., and 8:00 p. m. time points. Mice treated with 236 mg/day raloxifene for 4 weeks (Study 2) had elevated LH levels (4.4-fold compared to control), whereas mice exposed to 7.9 mg/kg/day raloxifene had a slight, nonsignificant increase in LH (2-fold compared to control). In both dose groups, LH levels were indistinguishable from controls 3 weeks after raloxifene treatment was discontinued. The ovaries in six of the eight mice treated with 7.9 mg/kg/day raloxifene had dilated and/or anovulatory follicles. One mouse in this group had a single hemorrhagic follicle; however, corpora lutea distribution was normal, indicating that ovulation was occurring. Raloxifene-treated mice in Study 1 and mice treated with a comparable raloxifene dose (236 mg/day) in Study 2 had histomorphological changes in the ovary indicative of arrested follicular maturation, including anovulatory hemorrhagic follicles, some developing follicles, and very few corpora lutea. At the end of the reversibility phase, hemorrhagic follicles were no longer evident and follicular maturation and corpora lutea distribution were normal. Raloxifene treatment in mice produces a dose-dependent, sustained elevation in serum LH levels and is associated with changes in ovarian follicular morphology. These changes are reversible upon discontinuation of raloxifene treatment.
Cohen
I R
IR
Toxicology Research Laboratories, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, IN 46140, USA. Cohen_Ilene_R@Lilly.com
Sims
M L
ML
Robbins
M R
MR
Lakshmanan
M C
MC
Francis
P C
PC
Long
G G
GG
D000818:Animals; D003338:Corpus Luteum / Q000187:drug effects / Q000502:physiology; D005260:Female; D007986:Luteinizing Hormone / Q000097:blood*; D051379:Mice; D006080:Ovarian Follicle / Q000187:drug effects / Q000254:growth & development; D010051:Ovarian Neoplasms / Q000097:blood / Q000139:chemically induced; D010053:Ovary / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D020849:Raloxifene Hydrochloride / Q000633:toxicity*; D020845:Selective Estrogen Receptor Modulators / Q000633:toxicity*
D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D007986:Luteinizing Hormone