Treatment with Bazedoxifene, a Selective Estrogen Receptor Modulator, Causes Regression of Endometriosis in a Mouse Model

Abstract

Endometriosis is a common estrogen-dependent disorder. Medical treatments currently consist of progestins or GnRH agonists; however, neither is fully effective and both entail significant side effects. Selective estrogen receptor (ER) modulators (SERM) have tissue-selective actions, acting as an ER agonist in some tissues and ER antagonist in others. The SERM bazedoxifene (BZA) effectively antagonizes estrogen-induced uterine endometrial stimulation without countering estrogenic effects in bone or central nervous system. These properties make it an attractive candidate for use in the treatment of endometriosis. Experimental endometriosis was created in reproductive-age CD-1 mice. After 8 wk, 10 animals received i.p. injections of BZA (3 mg/kg·d) for 8 wk, whereas 10 received vehicle control. Mice were killed, and implant size was assessed. The mean size of the implants after treatment was 60 mm(2) in the control group and 21 mm(2) in the BZA treatment group (P = 0.03). Quantitative PCR and immunohistochemical analysis were used to determine the effect on endometrial gene expression. PCNA, ERα, and LIF mRNA and protein expression were significantly decreased in endometrium of the treated group. Caspase 3 mRNA expression was increased. Expression of PR and Hoxa10 were not significantly altered by treatment. There was no evidence of ovarian enlargement or cyst formation. Decreased PCNA and ER expression demonstrated that the regression of endometriosis likely involved decreased estrogen-mediated cell proliferation. BZA may be an effective novel agent for the treatment of endometriosis due to greater endometrial-specific estrogen antagonism compared with other SERM.

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…In its early discovery, it displayed the prototypical SERM gene-selective activation phenotype, where it antagonized expression on a 2Â-ERE (estrogen response element) promoter, but agonized expression driven by a hepatic lipase promoter in the same cell line (Komm and Lyttle, 2001). Bazedoxifene antagonizes estrogen-stimulated proliferation of MCF-7 breast cancer cells with little to no effects in uterine and CNS tissue, and also maintains bone density, reduces cholesterol in rats, and causes regression of endometriosis in mice (Komm and Lyttle, 2001;Komm et al, 2005;Ronkin et al, 2005;Kulak et al, 2011). Bazedoxifene inhibits the proliferation of estrogen-dependent (MCF-7 and T47D) and estrogenindependent (MCF-7:5C and MCF-7:2A) cell lines (Lewis-Wambi et al, 2011).…”

Pharmacologic therapies in endometriosis: a systematic review

“…Daily oral administration of raloxifene to rats with induced endometriosis statistically significantly decreased the volume of implants after 14 days of treatment (170). Bazedoxifene, another SERM that was demonstrated to not stimulate the endometrium in postmenopausal women or to antagonize conjugated estrogeninduced uterine stimulation, was also capable of decreasing the mean size of endometriosis-like implants in rodents (96).…”

“…The tissue selective activity of the selective estrogen receptor modulators (SERMs) enables these molecules to have predominantly ER antagonism in the breast and uterus and ER agonism in the skeleton, on serum lipid metabolism, and on some coagulation factors. The SERM raloxifene, which has been shown to not stimulate endometrial proliferation in rats, was approved for the management of postmenopausal osteoporosis (96).…”

Treatment of Endometriosis with Non-Hormonal Agents: Review

“…Endometriyum üzerinde antagonist etki yaparlar. 17 Stratton ve ark. endometriyozis nedeni ile kronik pelvik ağrısı olan laparoskopik endometriyotik doku eksizyonu yapılan 92 hastanın 46'sına raloksifen uygulamışlardır.…”

“…Bazedoksifen kullanılan grupta, endometriyotik doku hacminin, ER alfa ve mRNA düzeylerinin istatistiksel olarak azaldığı bildirilmiştir. 17 …”