Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in male rats.
BACKGROUND
Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) with greater than 100-fold selectivity against all other steroid receptors and is a potentially superior treatment for postmenopausal osteoporosis. The purpose of this study was to evaluate the effects of lasofoxifene on male reproduction in rats in light of the known effects of estrogen modulating compounds on male reproductive ability.


METHODS
Lasofoxifene was administered to adult male rats at doses of 0.1, 1, 10, and 100 mg/kg for 66-70 consecutive days. After 28 days of dosing, male rats were cohabited with untreated female rats. Female rats were euthanized on gestation day 14 and a uterine examination was carried out for evaluation of reproductive parameters and embryo viability. Male rats were euthanized after 66-70 days of dosing and epididymal sperm motility and concentration were assayed. The testes, epididymides, prostate, and seminal vesicles were weighed and microscopically examined.


RESULTS
The duration of cohabitation was increased for 100 mg/kg males by 0.7 days. The number of males copulating and the number of implantation sites produced per copulation were reduced in the 10 and 100 mg/kg groups. Weights of the seminal vesicles and epididymides were reduced for all groups, although the testes weight and epididymal sperm motility and concentration were not affected by treatment. There were no microscopic findings in the male reproductive tissues.


CONCLUSIONS
The changes in male fertility and reproductive tissue weights after exposure to lasofoxifene are consistent with those previously described for estrogen receptor-modulating compounds.
Cappon
Gregg D
GD
Pfizer Global Research and Development, Groton, Connecticut 06340, USA. gregg_d_cappon@groton.pfizer.com
Horimoto
Masao
M
Hurtt
Mark E
ME
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects; D004822:Epididymis / Q000187:drug effects; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000187:drug effects; D008297:Male; D009929:Organ Size; D010024:Osteoporosis / Q000188:drug therapy; D018812:Paternal Exposure; D011759:Pyrrolidines / Q000009:adverse effects / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects / Q000633:toxicity*; D012669:Seminal Vesicles / Q000187:drug effects; D013081:Sperm Motility / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000009:adverse effects / Q000633:toxicity*; D013997:Time Factors
D004967:Estrogens; D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; C111332:Lasofoxifene