Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats.
BACKGROUND
Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM). With high affinity to the alpha and beta 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 F1 generation. Several developmental indices were evaluated in the F1 pups through post-natal day (PND) 21.


RESULTS
In the cyclicity study, all lasofoxifene-treated 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 F1 generation was adversely affected.


CONCLUSIONS
Lasofoxifene reversibly altered the estrous cycle and inhibited implantation, consistent with what would be expected from a member of the SERM class.
Terry
K K
KK
Pfizer Global Research and Development, Groton, Connecticut 06340, USA. ketti_k_terry@groton.pfizer.com
Cappon
G D
GD
Hurtt
M E
ME
Tassinari
M S
MS
Gupta
U
U
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D010064:Embryo Implantation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects; D004967:Estrogens / Q000378:metabolism; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D010024:Osteoporosis / Q000188:drug therapy; D036801:Parturition / Q000187:drug effects; D011247:Pregnancy / Q000187:drug effects; D011270:Pregnancy, Animal; D011759:Pyrrolidines / Q000009:adverse effects / Q000097:blood / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects / Q000633:toxicity*; D013764:Tetrahydronaphthalenes / Q000009:adverse effects / Q000097:blood / Q000633:toxicity*; D013997:Time Factors
D004967:Estrogens; D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; C111332:Lasofoxifene