Effects of various selective estrogen receptor modulators with or without conjugated estrogens on mouse mammary gland.
Selective estrogen receptor modulators (SERMs) are small molecules that, depending on the end point measured, may either function as estrogen receptor (ER) agonists or antagonize estrogens' agonist activity. A key feature of SERMs is the inhibition of ER agonist action on the uterus and mammary gland, but the degree of antagonism varies among compounds and end points. Bazedoxifene is a SERM that is being clinically evaluated both as a monotherapy for the prevention and treatment of osteoporosis and in combination with conjugated estrogens (CEs) for the treatment of menopausal symptoms and prevention of osteoporosis. The studies reported here compare the relative ER agonist and antagonist effects of three pharmacologically distinct SERMs (bazedoxifene, raloxifene, and lasofoxifene) on the ovariectomized mouse when administered alone or as a tissue-selective estrogen complex, a term used to describe the partnering of a SERM and one or more estrogens. At the minimum dose required to maximally reduce CE-stimulated uterine wet weight increase for each SERM, the degree of inhibition varied among the SERMs, with a rank order of bazedoxifene approximately raloxifene > lasofoxifene, in which only bazedoxifene was statistically similar to vehicle. In the mammary gland, in which amphiregulin mRNA and morphological effects were measured, bazedoxifene generally exhibited less agonist activity and was a more effective antagonist of CE than raloxifene or lasofoxifene. In summary, in an animal model evaluating estrogen-modulated uterine effects and mammary gland development, bazedoxifene exhibited less ER agonist activity than raloxifene or lasofoxifene, and, as a tissue-selective estrogen complex, bazedoxifene/CE demonstrated less mammary gland stimulation than raloxifene/CE and lasofoxifene/CE.
Peano
Bryan J
BJ
Department of Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania 19426, USA. bpeano01@yahoo.com
Crabtree
Judy S
JS
Komm
Barry S
BS
Winneker
Richard C
RC
Harris
Heather A
HA
D066258:Amphiregulin; D000818:Animals; D004305:Dose-Response Relationship, Drug; D066255:EGF Family of Proteins; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D007211:Indoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011759:Pyrrolidines / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D004966:Estrogens, Conjugated (USP); D006023:Glycoproteins; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; C111332:Lasofoxifene; D020849:Raloxifene Hydrochloride; C447119:bazedoxifene