Lasofoxifene enhances vaginal mucus formation without causing hypertrophy and increases estrogen receptor beta and androgen receptor in rats.
OBJECTIVE
Lasofoxifene, a new selective estrogen-receptor modulator (SERM), shows efficacy in vaginal and vulvar atrophy in postmenopausal women. Here, we sought to explore the possible mechanisms of action for this effect in comparison with other SERMs using an immature ovariectomized rat model.


METHODS
SERMs (lasofoxifene, raloxifene, and tamoxifen) and 17alpha-ethinyl estradiol were administered orally to immature ovariectomized rats daily for 1 or 4 days. Vaginal and uterine tissues were weighed and processed for histomorphometric measurements, vaginal mucopolysaccharide staining, and immunohistochemistry of 5-bromo-2'-deoxyuridine and steroid receptors. Receptor quantification was determined by a novel ultrasensitive enzyme-linked immunosorbent assay method.


RESULTS
Lasofoxifene and raloxifene showed a minimal increase in vaginal and uterine weight, epithelial cell proliferation, and epithelial thickness in comparison with estradiol and tamoxifen. Lasofoxifene significantly enhanced vaginal mucus formation in a dose-dependent manner. Vaginal progesterone receptor protein was increased fivefold by estradiol and all three SERMs tested. 17alpha-Ethinyl estradiol caused a significant decrease in estrogen receptor alpha, but no change with other treatments. Only lasofoxifene significantly increased vaginal estrogen receptor beta and androgen receptor protein levels.


CONCLUSIONS
These results demonstrated that lasofoxifene stimulated vaginal mucus formation without causing cell proliferation in the rat reproductive tract. These effects may be due to the increased vaginal estrogen receptor beta and androgen receptor levels. This cellular and molecular profile of lasofoxifene in the vagina may account for its efficacy in the treatment of vaginal and vulvar atrophy in postmenopausal women.
Wang
Xiao-Ning
XN
Pfizer Global Research and Development, Pfizer, Inc, Groton, CT 06340, USA. xiao.n.wang@pfizer.com
Simmons
Hollis A
HA
Salatto
Christopher T
CT
Cosgrove
Patricia G
PG
Thompson
David D
DD
D000284:Administration, Oral; D000818:Animals; D001284:Atrophy / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D009092:Mucous Membrane / Q000378:metabolism; D010052:Ovariectomy; D017698:Postmenopause; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism; D014621:Vagina / Q000187:drug effects* / Q000378:metabolism; D014623:Vaginal Diseases / Q000188:drug therapy / Q000473:pathology
D047629:Estrogen Receptor beta; D011759:Pyrrolidines; D011944:Receptors, Androgen; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; D013629:Tamoxifen; C111332:Lasofoxifene; D004997:Ethinyl Estradiol; D020849:Raloxifene Hydrochloride