Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats

Abstract

BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM). With high affinity to the a and b human estrogen receptors and greater potency than other SERMs, lasofoxifene is potentially a superior treatment for postmenopausal osteoporosis. In light of the known effects of estrogen-modulating compounds on female reproductive indices, two studies were conducted to evaluate the effects of lasofoxifene on female rat cyclicity, reproduction, and parturition. METHODS: One study evaluated effects of lasofoxifene on estrous cyclicity, and the second study assessed effects on implantation and parturition. In the cyclicity study, lasofoxifene was administered to female rats at doses of 0.1, 0.3, and 1.0 mg/kg/day for 14 consecutive days. After treatment, there was a 3-week reversibility phase followed by a mating phase. In the implantation study, lasofoxifene was administered to pregnant female rats at doses of 0.01, 0.03, and 0.1 mg/kg/day for 7 consecutive days (gestation day [GD] 0-6). Some animals were euthanized on GD 21, and the remainder of the group was allowed to deliver the F 1 generation. Several developmental indices were evaluated in the F 1 pups through post-natal day (PND) 21. RESULTS: In the cyclicity study, all lasofoxifenetreated females were anestrous by Study Day 7 (1.0 mg/kg) or 9 (0.3 and 0.1 mg/kg). The reversibility phase resulted in restoration of normal estrous cycles by the end of 1 (0.1 mg/kg) or 2 weeks (0.3 and 1.0 mg/kg). During the mating phase, no adverse effects occurred in pregnancy success or reproductive parameters. In the implantation study, all doses of lasofoxifene increased pre-and post-implantation losses, increased gestation length, and reduced litter size. None of the developmental parameters measured on the

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in male rats

“…It is also possible that lasofoxifene present in ejaculate caused a direct effect on the female reproductive tract. Lasofoxifene administered to female rats from GD 0-6 caused increased pre-implantation loss at doses as low as 0.01 mg/kg (Terry et al, 2004). Reduced number of implantation sites were noted for untreated females mated to males dosed at 10 or 100 mg/kg.…”

Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits

“…Whereas the rat exhibited a significant increase in late resorptions at the highest dosage (100 mg/kg), early resorptions were noted in the rabbit also at the high dose (3 mg/kg), suggesting that there may be species differences with respect to the windows of embryo/fetal sensitivity. In the reproductive toxicity assessment study of lasofoxifene in rat, no treatment-related changes in viable fetuses or in the percentage of pre-and post-implantation loss were noted, which probably reflects the 100-fold decrease in administered dose (100 mg/kg vs. 1 mg/kg; Terry et al, 2004). With raloxifene, a significant increase in late resorptions was also reported in the rat, albeit at a much lower dose of 10 mg/kg (Byrd and Francis, 1998).…”

“…This may reflect lasofoxifene-induced developmental delays, which have been reported after treatment between GD 0-6 in rats (Terry et al, 2004). Alternatively, decreased fetal body weights may be the result of fetotoxic effects.…”

“…1C). In a reproductive toxicity assessment of lasofoxifene, the slopes of the curves for body weight versus times across all treatment groups were similar during the recovery phase (Terry et al, 2004). In the current study, a significant decrease in weight gain after the treatment period (GD 19-28) was noted in the high-dose rabbits.…”

“…Importantly, increased systemic levels of somatostatin have been implicated in altered feeding behavior (reviewed in Aponte et al, 1984), altered taste preferences in rats (Scalera and Tarozzi, 1998), and decreased food consumption in rodents and primates (Lotter et al, 1981). Alternate explanations for the lasofoxifene-mediated hypophagy have also been proposed , Terry et al, 2004, Weisenburger et al, 2004. Of note, no clinical signs indicative of frank toxicity were observed in general toxicity studies conducted with similar doses of lasofoxifene (data not shown).…”