Effects of Various Selective Estrogen Receptor Modulators with or without Conjugated Estrogens on Mouse Mammary Gland

Abstract

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.

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…Preclinical data have suggested that the combination treatment of bazedoxifene and conjugated estrogens (CE) might lead to a more favorable benefit-risk profile in the treatment of menopause symptoms, including favorable vasomotor, lipid, and skeletal response with minimal stimulation in the uterus (Kharode et al, 2008;Peano et al, 2009). This combination therapy also shows efficacy in the treatment of osteoporosis in a manner that prevents uterine growth, with decreased uterine wet weight and lower cholesterol levels .…”

Current pharmacotherapy of osteoporosis

“…Moreover, there was no influence of bazedoxifene on the overgrowth of endometrium or myometrium. In the studies comparing the effect of bazedoxifene, raloxifene, and lasofoxifene on the breasts of the mice, the first medicine showed the lowest stimulation and turned out to be the most effective antagonist of influence of conjugated estrogens on the breast, which was confirmed by histopathological tests [17].…”

“…Dodatkowo wykazano brak wpływu stosowania bazedoxifenu na przerost nabłonka śluzówki macicy i myometrium. W badaniach porównujących wpływ bazedoxifenu, raloxyfenu i lasoxifenu na gruczoł piersiowy myszy, ten pierwszy wykazał najsłabszą stymulację i okazał się najbardziej efektywnym antagonistą wpływu skoniugowanych estrogenów na gruczoł piersiowy, co potwierdziły badania histopatologiczne [17].…”

Pharmacological Treatment of Osteoporosis

“…(Stovall & Pinkerton, 2008) Preclinical studies have shown that bazedoxifene antagonizes estrogen-induced uterine and mammary gland stimulation more effectively than other SERMs like raloxifene and lasofoxifene. (Peano et al, 2009;Kharode et al, 2008) A randomized, double-blind, placebocontrolled Phase III trial in 3,397 postmenopausal women examined the effect of bazedoxifene 10, 20, or 40 mg combined with conjugated estrogens 0.625 mg or 0.45 mg on bone and endometrium. In this trial, the bazedoxifene plus conjugated estrogen combination therapy showed a statistically significant increase in BMD and a decrease in bone biochemical turnover markers compared with placebo.…”